Compounds for the treatment of cancer and inflammatory disease

ABSTRACT

Provided herein are compounds that inhibit the phosphorylation of MAPK and thus are useful in compositions and methods for treating cancer and inflammatory disease.

This application claims the benefit of U.S. Provisional PatentApplication No. 62/271,185, filed Dec. 22, 2015, which is incorporatedby reference herein in its entirety.

1. FIELD

Provided herein are methods and compositions for treating cancer andinflammatory disease using the compounds described herein.

2. BACKGROUND

Pathobiology of Cancer

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia. Theneoplastic lesion may evolve clonally and develop an increasing capacityfor invasion, growth, metastasis, and heterogeneity, especially underconditions in which the neoplastic cells escape the host's immunesurveillance. Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

There is an enormous variety of cancers which are described in detail inthe medical literature. Examples include cancer of the lung, colon,rectum, pancreatic, prostate, breast, brain, and intestine. Theincidence of cancer continues to climb as the general population ages,as new cancers develop, and as susceptible populations grow. Atremendous demand therefore exists for new methods and compositions thatcan be used to treat patients with cancer.

Solid Tumors

Over 85% of human cancers are solid tumors, including carcinomas,sarcomas and lymphomas. Jain, et al. Int J Pharm Pharm Sci, 2011, Vol 3,Suppl 5, 45-51. Solid tumors are abnormal masses of tissue that may, butusually do not contain cysts or liquid areas. Solid tumors may be benign(not cancer), or malignant (cancer). Different types of solid tumors arenamed for the type of cells that form them. Examples of types solidtumors include, but are not limited to malignant melanoma, adrenalcarcinoma, breast carcinoma, renal cell cancer, carcinoma of thepancreas, non small-cell lung carcinoma (NSCLC) and carcinoma of unknownprimary.

The effectiveness of cancer therapy in solid tumors depends on adequatedelivery of the therapeutic agent to tumor cells. Inadequate deliverywould result in residual tumor cells, which in turn would lead toregrowth of tumors and possibly development of resistant cells. Inaddition, the long-standing problem of chemotherapy is the lack oftumor-specific treatments. Cancer chemotherapeutic agents are oftenadministered systemically. Following a systemic administration, drugdelivery to cells in solid tumors involves three processes, i.e.,transport within a vessel (e.g., blood circulation), transport acrossvasculature walls into surrounding tissues, and transport throughinterstitial space within a tumor. These processes are determined by thephysicochemical properties of a drug or particle (e.g., molecular orparticle size, diffusivity, drug binding to cellular macromolecules) andthe biologic properties of a tumor (e.g., tumor vasculature,extracellular matrix components, interstitial fluid pressure (IFP),tumor cell density, tissue structure and composition). Cancer drugdelivery is no longer simply wrapping the drug in new formulations fordifferent routes of delivery. Nanotechnology, polymer chemistry andelectronic engineering technologies are being brought for developingnovel methods of drug delivery. Various stages of tumor development canbe explained as follows:

a) Tumor evolution commences when a cell within a normal populationsustains a genetic mutation that expands its tendency to proliferatewhen it would normally rest.

b) Genetically altered cells and their offspring continue to appearnormal, but they reproduce excessively and lead to a condition termed toas hyperplasia. After some time (months or years) one in a million ofthese cells sustain additional mutation with subsequent loss of controlof cell growth.

c) The offspring of these cells not only proliferate excessively butalso appear abnormal in shape and in orientation. The tissue is now saidto exhibit a condition termed to as dysplasia. After some time, afurther mutation that alters cell behavior results.

d) The influenced and genetically altered cells turn still more abnormalin growth and appearance. If the tumor mass does not invade through anyboundaries between tissues, it is termed as an in situ tumor. This tumormay stay contained indefinitely, however, some cells may acquireadditional mutations.

e) A malignant or invasive tumor results if the genetic changes allowthe tumor mass to initiate invading underlying tissue and to cast offcells into the blood or lymph. The defector cells may install new tumorsloci (metastases) throughout the body.

Metastases represent the end products of a multistep cell-biologicalprocess termed the invasion-metastasis cascade, which involvesdissemination of cancer cells to anatomically distant organ sites andtheir subsequent adaptation to foreign tissue microenvironments. Each ofthese events is driven by the acquisition of genetic and/or epigeneticalterations within tumor cells and the co-option of nonneoplasticstromal cells, which together endow incipient metastatic cells withtraits needed to generate macroscopic metastases. Volastyan, S., et al.,Cell, 2011, vol. 147, 275-292.

Whereas surgical resection and adjuvant therapy can cure well-confinedprimary tumors, metastatic disease is largely incurable because of itssystemic nature and the resistance of disseminated tumor cells toexisting therapeutic agents. This explains why >90% of mortality fromcancer is attributable to metastases, not the primary tumors from whichthese malignant lesions arise.

Carcinomas are a type of cancer that develops from epithelial cells.Specifically, a carcinoma is a cancer that begins in a tissue that linesthe inner or outer surfaces of the body, and that generally arises fromcells originating in the endodermal or ectodermal germ layer duringembryogenesis. The term carcinoma has also come to encompass malignanttumors composed of transformed cells whose origin or developmentallineage is unknown (see cancer of unknown primary origin (CUP)), butthat possess certain specific molecular, cellular, and histologicalcharacteristics typical of epithelial cells. This may include theproduction of one or more forms of cytokeratin or other intermediatefilaments, intercellular bridge structures, keratin pearls, and/ortissue architectural motifs such as stratification orpseudo-stratification. Common malignancies, such as breast, colon, andlung cancer, are almost always carcinoma. Other types of carcinomasinclude squamous-cell carcinomas (oral cancers), lung cancers, breast(ductal) carcinoma, prostate (adenocarcinoma), colon and rectum(adenocarcinoma or squamous cell carcinoma), pancreatic(adenocarcinoma), ovarian, hepatocellular and renal cell carcinoma.

A sarcoma is a cancer that arises from transformed cells of mesenchymalorigin. Thus, malignant tumors made of cancellous bone, cartilage, fat,muscle, vascular, or hematopoietic tissues are, by definition,considered sarcomas. Sarcomas occur much less frequently in humans thancarcinomas. Types of sarcomas include, for example, osteosarcoma,chondrosarcoma, liposarcoma, and leiomyosarcoma.

Lymphoma refers to cancers that originate in the lymphatic system.Lymphoma is characterized by malignant neoplasms of lymphocytes—Blymphocytes and T lymphocytes (i.e., B-cells and T-cells). Lymphomagenerally starts in lymph nodes or collections of lymphatic tissue inorgans including, but not limited to, the stomach or intestines.Lymphoma may involve the marrow and the blood in some cases. Lymphomamay spread from one site to other parts of the body.

Such lymphomas include, but are not limited to, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous B-cell lymphoma, activated B-celllymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma(MCL), follicular center lymphoma, transformed lymphoma, lymphocyticlymphoma of intermediate differentiation, intermediate lymphocyticlymphoma (ILL), diffuse poorly differentiated lymphocytic lymphoma(PDL), centrocytic lymphoma, diffuse small-cleaved cell lymphoma(DSCCL), peripheral T-cell lymphomas (PTCL), cutaneous T-Cell lymphomaand mantle zone lymphoma and low grade follicular lymphoma.

Non-Hodgkin's lymphoma (NHL) is the fifth most common cancer for bothmen and women in the United States, with an estimated 63,190 new casesand 18,660 deaths in 2007. Jemal A, et al., CA Cancer J Clin 2007;57(1):43-66. The probability of developing NHL increases with age andthe incidence of NHL in the elderly has been steadily increasing in thepast decade, causing concern with the aging trend of the US population.Id. Clarke C A, et al., Cancer 2002; 94(7):2015-2023.

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately onethird of non-Hodgkin's lymphomas. While some DLBCL patients are curedwith traditional chemotherapy, the remainder die from the disease.Anticancer drugs cause rapid and persistent depletion of lymphocytes,possibly by direct apoptosis induction in mature T and B cells. See K.Stahnke. et al., Blood 2001, 98:3066-3073. Absolute lymphocyte count(ALC) has been shown to be a prognostic factor in follicular nonHodgkin's lymphoma and recent results have suggested that ALC atdiagnosis is an important prognostic factor in diffuse large B-celllymphoma. See D. Kim et al., Journal of Clinical Oncology, 2007 ASCOAnnual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement),2007: 8082.

Hematological Cancers

Leukemia refers to malignant neoplasms of the blood-forming tissues.Various forms of leukemias are described, for example, in U.S. Pat. No.7,393,862 and U.S. provisional patent application No. 60/380,842, filedMay 17, 2002, the entireties of which are incorporated herein byreference. Although viruses reportedly cause several forms of leukemiain animals, causes of leukemia in humans are to a large extent unknown.The Merck Manual, 944-952 (17th ed. 1999). Transformation to malignancytypically occurs in a single cell through two or more steps withsubsequent proliferation and clonal expansion. In some leukemias,specific chromosomal translocations have been identified with consistentleukemic cell morphology and special clinical features (e.g.,translocations of 9 and 22 in chronic myelocytic leukemia, and of 15 and17 in acute promyelocytic leukemia). Acute leukemias are predominantlyundifferentiated cell populations and chronic leukemias more mature cellforms.

Acute leukemias are divided into lymphoblastic (ALL) andnon-lymphoblastic (ANLL) types. The Merck Manual, 946-949 (17th ed.1999). They may be further subdivided by their morphologic andcytochemical appearance according to the French-American-British (FAB)classification or according to their type and degree of differentiation.The use of specific B- and T-cell and myeloid-antigen monoclonalantibodies are most helpful for classification. ALL is predominantly achildhood disease which is established by laboratory findings and bonemarrow examination. ANLL, also known as acute myelogenous leukemia oracute myeloblastic leukemia (AML), occurs at all ages and is the morecommon acute leukemia among adults; it is the form usually associatedwith irradiation as a causative agent.

Chronic leukemias are described as being lymphocytic (CLL) or myelocytic(CML). The Merck Manual, 949-952 (17th ed. 1999). CLL is characterizedby the appearance of mature lymphocytes in blood, bone marrow, andlymphoid organs. The hallmark of CLL is sustained, absolutelymphocytosis (>5,000/μL) and an increase of lymphocytes in the bonemarrow. Most CLL patients also have clonal expansion of lymphocytes withB-cell characteristics. CLL is a disease of middle or old age. In CML,the characteristic feature is the predominance of granulocytic cells ofall stages of differentiation in blood, bone marrow, liver, spleen, andother organs. In the symptomatic patient at diagnosis, the total whiteblood cell (WBC) count is usually about 200,000/μL, but may reach1,000,000/μL. CML is relatively easy to diagnose because of the presenceof the Philadelphia chromosome.

In addition to the acute and chronic categorization, neoplasms are alsocategorized based upon the cells giving rise to such disorder intoprecursor or peripheral. Precursor neoplasms include ALLs andlymphoblastic lymphomas and occur in lymphocytes before they havedifferentiated into either a T- or B cell. Peripheral neoplasms arethose that occur in lymphocytes that have differentiated into either T-or B-cells. Such peripheral neoplasms include, but are not limited to,B-cell CLL, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma,mantle cell lymphoma, follicular lymphoma, extranodal marginal zoneB-cell lymphoma of mucosa associated lymphoid tissue, nodal marginalzone lymphoma, splenic marginal zone lymphoma, hairy cell leukemia,plasmacytoma, diffuse large B-cell lymphoma and Burkitt lymphoma. Inover 95 percent of CLL cases, the clonal expansion is of a B celllineage. See Cancer: Principles & Practice of Oncology (3rd Edition)(1989) (pp. 1843 1847). In less than 5 percent of CLL cases, the tumorcells have a T-cell phenotype. Notwithstanding these classifications,however, the pathological impairment of normal hematopoiesis is thehallmark of all leukemias.

Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow.Normally, plasma cells produce antibodies and play a key role in immunefunction. However, uncontrolled growth of these cells leads to bone painand fractures, anemia, infections, and other complications. Multiplemyeloma is the second most common hematological malignancy, although theexact causes of multiple myeloma remain unknown. Multiple myeloma causeshigh levels of proteins in the blood, urine, and organs, including butnot limited to M-protein and other immunoglobulins (antibodies),albumin, and beta-2-microglobulin. M-protein, short for monoclonalprotein, also known as paraprotein, is a particularly abnormal proteinproduced by the myeloma plasma cells and can be found in the blood orurine of almost all patients with multiple myeloma.

The incidence of cancer continues to climb as the general populationages, as new cancers develop, and as susceptible populations grow. Atremendous demand therefore exists for new methods, treatments andcompositions that can be used to treat patients with cancer.

The role of mitogen-activated protein kinase (MAPK), such as MAPK1/2(ERK1/2), signaling in the development of cancer has been studiedextensively. The “MAPK pathway,” or the RAS-RAF-MEK-MAPK/ERK pathway,involves signaling and phosphorylation that plays a key role inregulation of cell growth differentiation, proliferation, apoptosis andmigration functions. MAPKs play an important role in the transmission ofextracellular signals into intracellular responses. Activation of MAPKresults from a three-kinase cascade consisting of a MAPK kinase kinase(MAPK3)(e.g., Raf, MLK, TAK) which phosphorylates and activates a MAPKkinase (e.g., MEK), which then phosphorylates and increases the activityof one or more MAPKs (e.g., ERK1/2). MAPK3s are regulated by growthfactor dependent Ras proteins. Activated MAPKs phosphorylate variousintracellular targets. Dhillon, et al., 2007, Oncogene, vol. 26,3279-3290.

Dysregulation or abnormal activation of the MAPK pathway has beenimplicated in human cancers. Therefore, inhibitors targeting the MAPKpathway have been the subject of intense study in recent years.Santarpia, et al., 2012, Expert Opin. Ther. Targets, vol. 16(1),103-119); Zaganjor, et al., 2011, Tocris Reviews, no. 35 (available athttp://www.komabiotech.co.kr/pdf/mapk_signaling review.pdf).

It has also been shown that mutations in genes encoding receptors (e.g.,EGFR) and signal transducers (e.g., RAS) upstream of MAPK, as well asdownstream kinases (e.g., BRAF) are implicated in human cancers.Burotto, et al., 2014, Cancer, 3446-3456. Thus, the MAPK pathwaypresents a logical target for anticancer drug development.

Methods of Treating Cancer

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, for example, Stockdale, 1998, Medicine, vol. 3, Rubensteinand Federman, eds., Chapter 12, Section IV). Recently, cancer therapycould also involve biological therapy or immunotherapy. All of theseapproaches may pose significant drawbacks for the patient. Surgery, forexample, may be contraindicated due to the health of a patient or may beunacceptable to the patient. Additionally, surgery may not completelyremove neoplastic tissue. Radiation therapy is only effective when theneoplastic tissue exhibits a higher sensitivity to radiation than normaltissue. Radiation therapy can also often elicit serious side effects.Hormonal therapy is rarely given as a single agent. Although hormonaltherapy can be effective, it is often used to prevent or delayrecurrence of cancer after other treatments have removed the majority ofcancer cells. Certain biological and other therapies are limited innumber and may produce side effects such as rashes or swellings,flu-like symptoms, including fever, chills and fatigue, digestive tractproblems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of cancer. A number of cancerchemotherapeutics act by inhibiting DNA synthesis, either directly orindirectly by inhibiting the biosynthesis of deoxyribonucleotidetriphosphate precursors, to prevent DNA replication and concomitant celldivision. Gilman et al., Goodman and Gilman's: The Pharmacological Basisof Therapeutics, Tenth Ed. (McGraw Hill, New York).

Despite availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubensteinand Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeuticagents are toxic, and chemotherapy causes significant and oftendangerous side effects including severe nausea, bone marrow depression,and immunosuppression. While targeted therapy with chemotherapeuticagents, in particular small molecules, may address some of these issues,they are not a panacea and do not resolve all such issues. See, e.g.,http://www.cancer.org/treatment/treatmentsandsideeffects/treatmrenttypes/targetedtherapy/targeted-therapy-toc.Additionally, even with administration of combinations ofchemotherapeutic agents, many tumor cells are resistant or developresistance to the chemotherapeutic agents. In fact, those cellsresistant to the particular chemotherapeutic agents used in thetreatment protocol often prove to be resistant to other drugs, even ifthose agents act by different mechanism from those of the drugs used inthe specific treatment. This phenomenon is referred to as multidrugresistance. Because of the drug resistance, many cancers proverefractory to standard chemotherapeutic treatment protocols.

Thus, there exists a significant need for compounds, compositions andmethods for treating, preventing and managing cancer.

Inflammatory Disease

In addition to ERK1/2, the MAPKs ERK5, c-Jun N-terminal kinases (JNKs)and p38 isoforms (p38α, p38β, p38γ and p38δ) have been shown to beimplicated in inflammatory response. Huang, et al. 2010, Protein Cell,1(3), 218-226. MAPKs have been shown to play important roles inembryonic development and adult tissue homeostasis, and in particularchronic inflammation and inflammation-associated cancer development.

JNKs (also referred to as stress-activated kinases (SAPKs)) areactivated by a MAPK3 cascade via MEK4 and MEK7. Manzoor, et al., 2012,J. Bacter. Virology, vol. 42(3), 189-195. JNKs regulate cellproliferation and apoptosis by activating various targets, including theAP-1 transcript factors. AP-is are activated by, e.g., cytokines,stress, growth factors and infections, and are involved in managingproliferation, differentiation and apoptosis.

Therefore, compounds that inhibit MAPKs are expected to be effective intreatment of inflammatory conditions.

3. SUMMARY

Provided herein are compounds which inhibit phosphorylation ofmitogen-activated protein kinases (MAPKs), cellular proliferation,secretion of IL-6 and TNF-α cytokines, and methods and compositions fortreating cancer and inflammatory diseases using such compounds. In oneembodiment, the compounds are inhibitors of MAPK1/2 phosphorylation. Asdiscussed above, phosphorylation of MAPKs, in particular MAPK1/2, isknown to be key in the development of many cancers and in theinflammatory response.

In one embodiment, the compounds provided herein are active in a MAPKcellular assay that measures phosphorylation inhibition and in cellularproliferation assays described herein.

4. DETAILED DESCRIPTION 4.1. Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there are a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

The singular forms “a,” “an,” and “the” include plural references,unless the context clearly dictates otherwise.

As used herein “subject” is an animal, such as a mammal, includinghuman, such as a patient.

As used herein, biological activity refers to the in vivo activities ofa compound or physiological responses that result upon in vivoadministration of a compound, composition or other mixture. Biologicalactivity, thus, encompasses therapeutic effects and pharmacokineticbehaviour of such compounds, compositions and mixtures. Biologicalactivities can be observed in in vitro systems designed to test for suchactivities.

As used herein, pharmaceutically acceptable derivatives of a compoundinclude, but are not limited to, salts, esters, enol ethers, enolesters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids,bases, clathrates, solvates or hydrates thereof. Such derivatives may bereadily prepared by those of skill in this art using known methods forsuch derivatization. The compounds produced may be administered toanimals or humans without substantial toxic effects and either arepharmaceutically active or are prodrugs. Pharmaceutically acceptablesalts include, but are not limited to, amine salts, such as but notlimited to N,N′-dibenzylethylenediamine, chloroprocaine, choline,ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and inorganic salts, such as but not limited to, sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates, mesylates, and fumarates.Pharmaceutically acceptable esters include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidicgroups, including, but not limited to, carboxylic acids, phosphoricacids, phosphinic acids, sulfonic acids, sulfinic acids and boronicacids. Pharmaceutically acceptable enol ethers include, but are notlimited to, derivatives of formula C═C(OR) where R is alkyl, alkenyl,alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enolesters include, but are not limited to, derivatives of formulaC═C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyland cycloalkyl. Pharmaceutically acceptable solvates and hydrates arecomplexes of a compound with one or more solvent or water molecules, or1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent orwater molecules.

As used herein, treatment means any manner in which one or more of thesymptoms of a disease or disorder are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compositions herein, such as use for treating inflammation.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular compound or pharmaceutical compositionrefers to any lessening, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe composition.

As used herein, and unless otherwise indicated, the terms “manage,”“managing” and “management” encompass preventing the recurrence of thespecified disease or disorder in a patient who has already suffered fromthe disease or disorder, and/or lengthening the time that a patient whohas suffered from the disease or disorder remains in remission. Theterms encompass modulating the threshold, development and/or duration ofthe disease or disorder, or changing the way that a patient responds tothe disease or disorder.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse in an assay that measures such response.

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, or be stereoisomeric ordiastereomeric mixtures. As such, one of skill in the art will recognizethat administration of a compound in its (R) form is equivalent, forcompounds that undergo epimerization in vivo, to administration of thecompound in its (S) form.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter enzymatic and biological activities of the substance.Methods for purification of the compounds to produce substantiallychemically pure compounds are known to those of skill in the art. Asubstantially chemically pure compound may, however, be a mixture ofstereoisomers. In such instances, further purification might increasethe specific activity of the compound. The instant disclosure is meantto include all such possible isomers, as well as, their racemic andoptically pure forms. Optically active (+) and (−), (R)- and (S)-, or(D)- and (L)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques, such as chiralreverse phase HPLC. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. is usedas is generally understood by those of skill in this art.

As used herein, alkyl, alkenyl and alkynyl carbon chains, if notspecified, contain from 1 to 20 carbons, or 1 to 16 carbons, and arestraight or branched. Alkenyl carbon chains of from 2 to 20 carbons, incertain embodiments, contain 1 to 8 double bonds, and the alkenyl carbonchains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 doublebonds. Alkynyl carbon chains of from 2 to 20 carbons, in certainembodiments, contain 1 to 8 triple bonds, and the alkynyl carbon chainsof 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds.Exemplary alkyl, alkenyl and alkynyl groups herein include, but are notlimited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl,sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl,ethenyl, propenyl, butenyl, pentenyl, acetylenyl and hexynyl. As usedherein, lower alkyl, lower alkenyl, and lower alkynyl refer to carbonchains having from about 1 or about 2 carbons up to about 6 carbons. Asused herein, “alk(en)(yn)yl” refers to an alkyl group containing atleast one double bond and at least one triple bond.

As used herein, “heteroalkyl” refers to a straight or branched aliphatichydrocarbon group having, inserted in the hydrocarbon chain one or moreoxygen, sulfur, including S(═O) and S(═O)₂ groups, or substituted orunsubstituted nitrogen atoms, including —NR— and —N⁺RR— groups, wherethe nitrogen substituent(s) is(are) alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, S(═O)₂R′ or COR′, where R′ is alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, OY or —NYY′, where Y and Y′ are eachindependently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl orheterocyclyl, in one embodiment having from 1 to about 20 atoms, inanother embodiment having from 1 to 12 atoms in the chain.

As used herein, “cycloalkyl” refers to a saturated mono- or multicyclicring system, in certain embodiments of 3 to 10 carbon atoms, in otherembodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl referto mono- or multicyclic ring systems that respectively include at leastone double bond and at least one triple bond. Cycloalkenyl andcycloalkynyl groups may, in certain embodiments, contain 3 to 10 carbonatoms, with cycloalkenyl groups, in further embodiments, containing 4 to7 carbon atoms and cycloalkynyl groups, in further embodiments,containing 8 to 10 carbon atoms. The ring systems of the cycloalkyl,cycloalkenyl and cycloalkynyl groups may be composed of one ring or twoor more rings which may be joined together in a fused, bridged orspiro-connected fashion. “Cycloalk(en)(yn)yl” refers to a cycloalkylgroup containing at least one double bond and at least one triple bond.In some embodiments, the cycloalkyl ring is unsaturated or partiallysaturated.

As used herein, “carbocyclic” refers to a mono- or multicyclic ringsystem, in which all of the atoms composing the ring are carbon atoms,such as benzene or cyclopropane. In some embodiments, the carbocyclicring is unsaturated or partially saturated.

As used herein, “substituted alkyl,” “substituted alkenyl,” “substitutedalkynyl,” “substituted cycloalkyl,” “substituted cycloalkenyl,” and“substituted cycloalkynyl” refer to alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl and cycloalkynyl groups, respectively, that are substitutedwith one or more substituents, in certain embodiments one to three orfour substituents, where the substituents are as defined herein, in oneembodiment selected from Q.

As used herein, “aryl” refers to aromatic monocyclic or multicyclicgroups containing from 6 to 19 carbon atoms. Aryl groups include, butare not limited to groups such as fluorenyl, substituted fluorenyl,phenyl, substituted phenyl, naphthyl and substituted naphthyl.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system, in certain embodiments, of about 5 to about 15members where one or more, in one embodiment 1 to 3, of the atoms in thering system is a heteroatom, that is, an element other than carbon,including but not limited to, nitrogen, oxygen or sulfur. The heteroarylgroup may be optionally fused to a benzene ring. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl andisoquinolinyl.

As used herein, “heterocyclyl” or “heterocyclic” refers to a monocyclicor multicyclic non-aromatic ring system, in one embodiment of 3 to 10members, in another embodiment of 4 to 7 members, in a furtherembodiment of 5 to 6 members, where one or more, in certain embodiments,1 to 3, of the atoms in the ring system is a heteroatom, that is, anelement other than carbon, including but not limited to, nitrogen,oxygen or sulfur. In embodiments where the heteroatom(s) is(are)nitrogen, the nitrogen is optionally substituted with alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino,amidino, sulfonyl or the nitrogen may be quaternized to form an ammoniumgroup where the substituents are selected as above. In some embodiments,the heterocyclyl ring is saturated. In some embodiments, theheterocyclyl ring is unsaturated or partially saturated.

As used herein, “substituted aryl,” “substituted heteroaryl” and“substituted heterocyclyl” refer to aryl, heteroaryl and heterocyclylgroups, respectively, that are substituted with one or moresubstituents, in certain embodiments one to three or four substituents,where the substituents are as defined herein, in one embodiment selectedfrom Q.

As used herein, “aralkyl” or “arylalkyl” refers to an alkyl group inwhich one of the hydrogen atoms of the alkyl is replaced by an arylgroup.

As used herein, “heteroaralkyl” refers to an alkyl group in which one ofthe hydrogen atoms of the alkyl is replaced by a heteroaryl group.

As used herein, “halo”, “halogen” or “halide” refers to F, Cl, Br or I.

As used herein, pseudohalides or pseudohalo groups are groups thatbehave substantially similar to halides. Such compounds can be used inthe same manner and treated in the same manner as halides. Pseudohalidesinclude, but are not limited to, cyano, thiocyanate, selenocyanate,trifluoromethoxy, and azide.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by halogen. Such groups include,but are not limited to, chloromethyl, trifluoromethyl and1-chloro-2-fluoroethyl.

As used herein, “haloalkoxy” refers to RO in which R is a haloalkylgroup.

As used herein, “carboxy” refers to a divalent radical, —C(O)O—.

As used herein, “aminocarbonyl” refers to —C(O)NH₂.

As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in which R isalkyl, including lower alkyl. As used herein, “dialkylaminocarbonyl”refers to —C(O)NR′R in which R′ and R are independently alkyl, includinglower alkyl; “carboxamide” refers to groups of formula —NR′COR in whichR′ and R are independently alkyl, including lower alkyl.

As used herein, “arylalkylaminocarbonyl” refers to —C(O)NRR′ in whichone of R and R′ is aryl, including lower aryl, such as phenyl, and theother of R and R′ is alkyl, including lower alkyl.

As used herein, “arylaminocarbonyl” refers to —C(O)NHR in which R isaryl, including lower aryl, such as phenyl.

As used herein, “hydroxycarbonyl” refers to —COOH.

As used herein, “alkoxycarbonyl” refers to —C(O)OR in which R is alkyl,including lower alkyl.

As used herein, “aryloxycarbonyl” refers to —C(O)OR in which R is aryl,including lower aryl, such as phenyl.

As used herein, “alkoxy” and “alkylthio” refer to RO— and RS—, in whichR is alkyl, including lower alkyl.

As used herein, “aryloxy” and “arylthio” refer to RO— and RS—, in whichR is aryl, including lower aryl, such as phenyl.

Where the number of any given substituent is not specified (e.g.,“haloalkyl”), there may be one or more substituents present. Forexample, “haloalkyl” may include one or more of the same or differenthalogens.

Where substitution is not specified (e.g., “aryl”), there may be one ormore substituents present. For example, “aryl” may include a“substituted aryl” group. In some embodiments, each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aralkyl,heteroaryl, and heterocyclyl is optionally substituted with one or moresubstituents, in one embodiment one, two, three or four substituents Q,where each Q is independently selected from (a) deuterium, cyano, halo,and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each of whichis further optionally substituted with one or more, in one embodiment,one, two, three, or four, substituents Q^(a); and (c) —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))R^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a); or (iii) R^(b)and R^(c) together with the N atom to which they are attached formheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) deuterium, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR_(f)R^(g), —OC(═NR^(e))NR_(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR_(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(b))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR, —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g),and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heterocyclyl. In some embodiments, two Qsubstituents together with the atoms to which they are attached, mayform a fused ring system.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, the IUPAC-IUB Commissionon Biochemical Nomenclature (see, (1972) Biochem. 11:942-944), or theIUPAC Nomenclature of Organic Chemistry (see, Favre H A and Powell W H,Nomenclature of Organic Chemistry: IUPAC Recommendations and PreferredNames 2013, Cambridge, UK: The Royal Society of Chemistry, 2013: PrintISBN 978-0-85404-182-4, PDF eISBN 978-1-84973-306-9, DOI10.1039/9781849733069; Nomenclature of Organic Chemistry, Sections A, B,C, D, E, F, and H, Pergamon Press, Oxford, 1979. Copyright 1979 IUPAC;and A Guide to IUPAC Nomenclature of Organic Compounds (Recommendations1993), 1993, Blackwell Scientific publications, Copyright 1993 IUPAC).

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician. A therapeutically effectiveamount of a compound provided herein can be administered in one dose(i.e., a single dose administration) or divided and administered overtime (i.e., continuous administration or multiple sub-doseadministration). Single dose administration, continuous administration,or multiple sub-dose administration can be repeated, for example, tomaintain the level of the compound in a biological molecule (e.g., aprotein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 22nd ed.; Loyd et al., Eds.; ThePharmaceutical Press, 2012; Handbook of Pharmaceutical Excipients, 7thed.; Rowe et al., Eds.; The Pharmaceutical Press, 2012; Handbook ofPharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse InformationResources, Inc., 2007; Pharmaceutical Preformulation and Formulation,2nd ed.; Gibson Ed.; CRC Press LLC, 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%>, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The term “percent by weight” or “% by weight” refers to the weight of aspecified component (e.g., an active compound or excipient) in acomposition (e.g., a pharmaceutical composition) as a percentage of thetotal weight of the composition. Thus, the sum of the weight percentagesof all the components in a composition is 100%.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a condition,disorder, or disease. As used herein, “active ingredient” and “activesubstance” may be an optically active isomer or an isotopic variant of acompound described herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, no less than about 94%, no less than about 95%,no less than about 96%, no less than about 97%, no less than about 98%,no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, the compound comprises about 95% or moreof one enantiomer and about 5% or less of the other enantiomer based onthe total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “isotopic variant” refers to a compound that contains anunnatural proportion of an isotope at one or more of the atoms thatconstitute such compounds. In certain embodiments, an “isotopic variant”of a compound contains unnatural proportions of one or more isotopes,including, but not limited to, hydrogen (¹H), deuterium (²H), tritium(⁶H), carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C), carbon-14(¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N),oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O),oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), fluorine-18 (¹⁸F), phosphorus-31(³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32 (³²S),sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36 (³⁶S),chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (¹²³I), iodine-125 (¹²⁵I)iodine-127 (¹²⁷I), iodine-129 (¹²⁹I), and iodine-131 (¹³¹I). In certainembodiments, an “isotopic variant” of a compound is in a stable form,that is, non-radioactive. In certain embodiments, an “isotopic variant”of a compound contains unnatural proportions of one or more isotopes,including, but not limited to, hydrogen (¹H), deuterium (²H), carbon-12(¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-16(¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F),phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S),sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certainembodiments, an “isotopic variant” of a compound is in an unstable form,that is, radioactive. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of one or more isotopes,including, but not limited to, tritium (³H), carbon-11 (¹¹C), carbon-14(¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18(¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S),chlorine-36 (³⁶Cl), iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-129(¹²⁹I), and iodine-131 (¹³¹I). It will be understood that, in a compoundas provided herein, any hydrogen can be ²H, for example, or any carboncan be ¹³C, as example, or any nitrogen can be ¹⁵N, as example, and anyoxygen can be ¹⁸O, where feasible according to the judgment of one ofskill. In certain embodiments, an “isotopic variant” of a compoundcontains unnatural proportions of deuterium. In some embodiments, apharmaceutically acceptable derivative of a compound is an isotopicvariant.

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which present in stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

The phrase “an isotopic variant thereof, or a pharmaceuticallyacceptable salt thereof; or a pharmaceutically acceptable solvatethereof” has the same meaning as the phrase “an isotopic variant of thecompound referenced therein; or a pharmaceutically acceptable salt ofthe compound referenced therein; or a pharmaceutically acceptable saltof an isotopic variant of the compound referenced therein; or apharmaceutically acceptable solvate of the compound referenced therein;or a pharmaceutically acceptable solvate of an isotopic variant of thecompound referenced therein; or a pharmaceutically acceptable solvate ofa pharmaceutically acceptable salt of the compound referenced therein;or a pharmaceutically acceptable solvate of a pharmaceuticallyacceptable salt of an isotopic variant of the compound referencedtherein or its variant or its variant.”

4.2. Compounds for Use in Compositions and Methods

Provided herein are compounds which inhibit phosphorylation of MAPK, inparticular MAPK1/2, cellular proliferation, secretion of IL-6 and TNF-αcytokines, which are therefore useful in compositions and methods oftreating cancer and inflammatory diseases.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula I

or pharmaceutically acceptable derivatives thereof,

wherein R¹ and R² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

X is O, S or NR⁵.

In another embodiment, the compound of Formula I is a compound ofFormula Ia:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is selected from the group consisting of H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, OR³, andNR⁶R⁷;

wherein R^(2a) is selected from the group consisting of H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

X is O, S or NR⁵.

In another embodiment, the compound of Formula I is a compound ofFormula Ia or pharmaceutically acceptable derivatives thereof, wherein:

R^(1a) is selected from the group consisting of H, phenyl, pyridinyl, orfrom one of the following:

R^(2a) is aryl or heteroaryl; and X is NH or S.

In one embodiment, the compound of Formula Ia is:

In another embodiment, the compound of Formula I is a compound ofFormula Ib:

or pharmaceutically acceptable derivatives thereof,

wherein R^(2b) is selected from the group consisting of alkyl, aryl,cycloalkyl, heterocyclyl and heteroaryl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached;

p is 0-2; and

X is O or NR⁵.

In another embodiment, the compound of Formula I is a compound ofFormula Ib or pharmaceutically acceptable derivatives thereof, wherein:

R⁶ and R⁷ are independently selected from hydrogen, methyl, isopropyl,phenyl, cyclopropyl, adamantyl, or selected from one of the following:

wherein phenyl is optionally substituted with one, two, or threesubstituents each selected from halogen, and R⁶ and R⁷ are combined toform a cyclic structure including the nitrogen atom to which they areboth attached, wherein the cyclic structure is selected from one of thefollowing:

R and R′ are independently selected from hydrogen and methyl; and

X is O or NH.

In one embodiment, the compound of Formula Ib is:

In another embodiment, the compound of Formula I is a compound ofFormula Ic:

or pharmaceutically acceptable derivatives thereof,

R^(3c) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl orarylcarbonyl;

R^(4c) is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached;

p is 0-2; and

X is O or NR⁵.

In another embodiment, the compound of Formula I is a compound wherein:

R^(3c) is phenyl or R^(3c), R and R′ are combined to form a cyclicstructure, as shown below

wherein phenyl is optionally substituted with one, two, or threesubstituents each selected from halogen, cyano, and methyl;

R^(4c) is selected from one of the following;

R and R′ are independently selected from hydrogen and methyl, or R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

X is O or N-phenyl.

In one embodiment, the compound of Formula Ic is:

In another embodiment, the compound of Formula I is a compound ofFormula Id:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1d) is selected from the group consisting of alkyl, aryl,cycloalkyl, heterocyclyl, heteroaryl and SR⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(4d) is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

X is O, S or NR⁵.

In another embodiment, the compound of Formula I is a compound ofFormula Id wherein:

R^(1d) is selected from one of the following:

R^(4d) is selected from one of the following:

X is O or S.

In one embodiment, the compound of Formula Id is:

In another embodiment, the compound of Formula I is a compound ofFormula Ie:

wherein R^(2e) is selected from the group consisting of aryl,heteroaryl, arylalkyl or heteroarylalkyl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(4e) is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment of Formula Ie, the compound of Formula Ie is acompound wherein:

R^(2e) is selected from the group consisting of furyl, pyridinyl,phenyl, and naphthylmethyl,

wherein phenyl is substituted with methyl;

R^(4e) is selected from one of the following:

R⁵ is hydrogen, propyl, cyclohexyl or phenyl; and

p is 0-2.

In one embodiment, the compound of Formula Ie is:

In one embodiment, the compound of Formula I is selected with theproviso that the compound is not

In one embodiment, the compound of Formula Ia is selected with theproviso that the compound is not

In one embodiment, the compound of Formula I is selected with theproviso that if X is NH and R¹ is phenyl, then R² is not pyridyl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula II

or pharmaceutically acceptable derivatives thereof,

wherein R¹ and R² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment, the compound of Formula II is a compound ofFormula IIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is heterocyclyl or NR⁶R⁷;

wherein R^(2a) is H, aryl, or heteroaryl;

R^(5a) is alkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached.

In another embodiment of Formula IIa, the compound of Formula II is acompound wherein:

R^(1a) is amino, or as depicted below:

wherein R^(2a) is H or pyridinyl;

R^(5a) is isopropyl, or as depicted below:

In one embodiment, the compound of Formula IIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula III:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

X is O or S; or X is NR, wherein R forms a non-aromatic ring with one ofthe carbon atoms adjacent to the nitrogen on the five-membered ring towhich it is attached.

In another embodiment of Formula III, the compound of Formula III is acompound wherein

R¹ is phenyl or as depicted below:

R² is methyl or as depicted below:

p is 0-2; and

X is O; or X is NR, wherein R forms a seven-membered ring with one ofthe carbon atoms adjacent to the nitrogen on the five-membered ring towhich it is attached.

In one embodiment, the compound of Formula III is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is selected from the group consisting of H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, OR³, andNR⁶R⁷;

wherein R^(2a) is aryl or heteroaryl;

wherein R^(8a) are is H or alkyl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached.

In another embodiment of Formula IIIa, a compound of Formula IIIa is acompound wherein:

R^(1a) is selected from the group consisting of pyridinyl, isoxazolyl,phenyl, benzodioxalyl, quinoxalinyl, pyrolidinonyl, aminoalkyl,benzimidazolyl, benzyl, benzofuranyl, and one of the following:

wherein pyridinyl, isoxazolyl, phenyl, furanyl and benzyl is optionallysubstituted with one or two substituents each selected from methyl,halogen, methoxy, benzodioxalyl, pyridinyl, tetrazolyl;

R^(2a) is pyridinyl;

R^(8a) is hydrogen; and

R⁵ is hydrogen.

In one embodiment, the compound of Formula IIIa is:

In another embodiment of Formula IIIa, a compound of Formula IIa is acompound wherein:

R^(1a) is selected from the group consisting of:

R^(2a) is pyridinyl;

R^(8a) is hydrogen; and

R⁵ is hydrogen.

In one embodiment, the compound of Formula IIIa is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is OR³, NRC(O)R⁴ or NR⁶R⁷;

R^(2b) is OR³, aryl or heteroaryl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

R″ and R′″ are independently selected from hydrogen and alkyl, and R″and R′″ are combined to form a cyclic structure including the carbonatom to which they are both attached.

In another embodiment of Formula IIIb, a compound of Formula IIb is acompound wherein:

R^(1b) is OR³, or phenyl;

R^(2b) is OR³, or as follows:

R³ is phenyl,

wherein phenyl is optionally substituted with one or two substituentseach selected from methoxy, 1,1,1-trifluoroporpan-2-ol, and halogen

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁸ is hydrogen; and

R and R′ are hydrogen.

In one embodiment, the compound of Formula IIIb is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIc:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1c) is aryl, or heteroaryl;

R^(2c) is SR⁴, NR⁵C(O)R⁴ or NR⁶R⁷;

R^(8c) is H or alkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

X is O or S.

In another embodiment of Formula III, a compound of Formula IIIc is acompound wherein

R^(1c) is SR⁴, phenyl, or pyridinyl, or thienyl;

wherein phenyl is optionally substituted with one or two substituentsselected from methyl, methoxy, ethoxy, halogen;

R^(2c) is SR⁴, CH₂SR⁴, or selected from the following:

R^(8c) is H or methyl;

R⁴ is selected from the following:

R and R′ are hydrogen; and

X is O or S.

In another embodiment of Formula III, a compound of Formula IIIc is acompound wherein

R^(1c) is SR⁴, phenyl, or pyridinyl, or thienyl;

wherein phenyl is optionally substituted with one or two substituentsselected from methyl, methoxy, ethoxy, halogen;

R^(2c) is SR⁴, CH₂SR⁴, or selected from the following:

R^(8c) is H or methyl;

R⁴ is selected from the following:

R and R′ are hydrogen; and

X is O or S.

In one embodiment, the compound of Formula IIIc is:

In another embodiment, the compound of Formula III is a compound ofFormula IIId:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1d) is alkyl, cycloalkyl, S(O)_(p)R⁴, NR⁵C(O)R⁴, or NR⁶R⁷;

R^(2d) is aryl or heteroaryl;

R^(8d) is H or alkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached.

In another embodiment of Formula IIId, a compound of Formula IIId is acompound wherein:

wherein R^(1d) is cyclopropyl, phenyl, S(O)₂R⁴, NR⁵C(O)R⁴, or NR⁶R⁷,

wherein phenyl is optionally substituted with one or two substituentseach selected from hydroxyl and CONH₂;

R^(2d) is phenyl or as depicted below:

wherein phenyl is optionally substituted with 1-3 substituents eachselected from methoxy, halogen, methyl, and hydroxyl;

R^(8d) is hydrogen, methyl, or CH₂CH₂CO₂CH₃;

R⁴ is phenyl or selected from one of the following:

wherein phenyl is optionally substituted with two halogens;

R⁵ is hydrogen; and

R⁶ and R⁷ are independently selected from hydrogen, cyclohexyl, and R⁶and R⁷ are combined to form a six-membered cyclic structure includingthe nitrogen atom to which they are both attached.

In another embodiment of Formula IIId, a compound of Formula IIId is acompound wherein:

wherein R^(1d) is cyclopropyl, phenyl, S(O)₂R⁴, NRC(O)R⁴, or NR⁶R⁷,

wherein phenyl is optionally substituted with one or two substituentseach selected from hydroxyl and CONH₂;

R^(2d) is phenyl or as depicted below:

wherein phenyl is optionally substituted with 1-3 substituents eachselected from methoxy, halogen, methyl, and hydroxyl;

R^(8d) is hydrogen, methyl, or CH₂CH₂CO₂CH₃;

R⁴ is phenyl or selected from one of the following:

wherein phenyl is optionally substituted with two halogens;

R⁵ is hydrogen; and

R⁶ and R⁷ are independently selected from hydrogen, cyclohexyl, and R⁶and R⁷ are combined to form a six-membered cyclic structure includingthe nitrogen atom to which they are both attached.

In one embodiment, the compound of Formula IIId is:

In one embodiment, the compound of Formula IIId is:

In another embodiment, the compound of Formula IId is:

In another embodiment, the compound of Formula III is compound ofFormula IIIe:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1e) is aryl or heteroaryl;

R^(2e) is H or alkyl;

R^(6e) and R^(7e) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached; and

X is O or S.

In another embodiment of Formula IIIe, a compound of Formula IIIe is acompound wherein:

R^(1e) is pyridinyl, phenyl;

wherein phenyl is optionally substituted with one substituent selectedfrom halogen, and ethyl;

R^(2e) is methyl or hydrogen;

R^(6e) and R^(7e) are independently selected from hydrogen or one of thefollowing

and R^(6e) and R^(7e) are combined to form a piperidine including thenitrogen atom to which they are both attached, and this piperidinyl ringis substituted with phenyl; and

X is O or S.

In another embodiment of Formula IIIe, a compound of Formula IIIe is acompound wherein:

R^(1e) is pyridinyl, phenyl;

wherein phenyl is optionally substituted with one substituent selectedfrom halogen, and ethyl;

R^(2e) is methyl or hydrogen;

R^(6e) and R^(7e) are independently selected from hydrogen or one of thefollowing

and R^(6e) and R^(7e) are combined to form a piperidine including thenitrogen atom to which they are both attached, and this piperidinyl ringis substituted with phenyl; and

X is O or S.

In one embodiment, the compound of Formula IIIe is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIf:

or pharmaceutically acceptable derivatives thereof,

wherein R^(2f) is H or alkyl;

R^(4f) is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

R^(6f) and R^(7f) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached.

In another embodiment of Formula IIIf, a compound of Formula IIIf is acompound wherein

R^(2f) is H or methyl;

R^(4f) is methyl or ethyl; and

R^(6f) and R^(7f) are independently selected from cyclopropyl, ethyl, orone of the following

In one embodiment, the compound of Formula IIIf is:

In another embodiment, the compound of Formula III is a compound ofFormula IIIg:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1g) is aryl or heteroaryl;

R^(9g) and R^(7g) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached; and

R^(8g) is H or alkyl.

In another embodiment of Formula IIIg, a compound of Formula IIIg is acompound wherein:

R^(1g) is phenyl, or pyrimidinyl;

wherein phenyl is optionally substituted with one or two substituentseach selected from methoxy, halogen, or propyl;

R^(6g) and R^(7g) are independently selected from hydrogen or one of thefollowing:

R⁶ and R⁷ are combined to form a cyclic structure including the nitrogenatom to which they are both attached, as depicted below:

and

R^(8g) is H.

In one embodiment, the compound of Formula IIIg is:

In one embodiment, the compound of Formula III is selected with theproviso that the compound is not

In one embodiment, the compound of Formula IIId is selected with theproviso that the compound is not

In one embodiment, the compound of Formula III is selected with theproviso that if X is S, then R¹ is not optionally substitutedmorpholino, thiomorpholino, piperinyl, indolyl, pyridyl, thienyl,aminophenyl, phenyl, methoxyphenyl, chloromethyl, amido,imadazothiazolyl, piperizinyl, pyrrolidino, thiazolyl, imidazolyl, orpyrazolyl.

In one embodiment, the compound of Formula IIId is selected with theproviso that R^(1d) is not optionally substituted morpholino,thiomorpholino, piperinyl, indolyl, aminophenyl, chloromethyl, amido,imadazothiazolyl, piperizinyl, pyrrolidino, imidazolyl or pyrazolyl.

In one embodiment, the compound of Formula III is selected with theproviso that if X is S, then R² is not naphthyl or tetrahydronaphthyl.

In one embodiment, the compound of Formula III is selected with theproviso that if X is O and R¹ is phenyl or thienyl, then R⁸ is notmorpholino.

In one embodiment, the compound of Formula III is selected with theproviso that if X is NH and R¹ is heteroaryl, then R⁸ is not morpholino.

In one embodiment, the compound of Formula IIId is selected with theproviso that R^(2d) is not naphthyl or tetrahydronaphthyl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula IV:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

X is O or NR⁵.

In another embodiment, the compound of Formula IV is a compound ofFormula IVa:

or pharmaceutically acceptable derivatives thereof,

wherein R² is H or alkyl;

R^(8a) is aryl or heteroaryl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R^(6a) and R^(7a) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached; and

X is O or NR⁵.

In another embodiment, the compound of Formula IVa is a compound wherein

R^(2a) is H;

R^(8a) is phenyl, pyridinyl, or as shown below

wherein phenyl is optionally substituted with a halogen;

R^(6a) and R^(7a) are independently selected from H, pyridinyl,cyclopropyl, cyclopentyl, or one of the following:

X is O or NH, or NCH₃.

In one embodiment, the compound of Formula IVa is:

In another embodiment, the compound of Formula IV is a compound ofFormula IVb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(8a) is H or alkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R^(6b) and R^(7b) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6b) and R^(7b)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

X is O or NR⁵.

In another embodiment, Formula IVb is:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is H or alkyl;

R^(8b) is H or alkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R^(6b) and R^(7b) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6b) and R^(7b)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

X is O or NR⁵.

In another embodiment of Formula IVb, a compound of Formula IVb is acompound wherein

R^(1b) is methyl;

R^(8b) is methyl;

R^(6b) and R^(7b) are independently selected from hydrogen, methyl, orone of the following:

R and R′ are hydrogen,

X is O or NR⁵; and

R⁵ is benzyl

wherein benzyl is substituted with a halogen.

In one embodiment, the compound of Formula IVb is:

In another embodiment, the compound of Formula IV is a compound ofFormula IVc:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1c) is aryl or heteroaryl;

R^(2c) is H, halo or alkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R^(6c) and R^(7c) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6c) and R^(7c)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

X is O or NR⁵.

In another embodiment of Formula IVc, a compound of Formula IVc is acompound wherein

R^(1c) is phenyl

wherein phenyl is optionally substituted with methyl;

R^(2c) is H or a halogen;

R^(6c) and R^(7c) are independently selected from cyclopropyl or one ofthe following:

and

X is O or NH.

In one embodiment, the compound of Formula IVc is:

In another embodiment, the compound of Formula IVd:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1d) is OR^(3a) or NR^(6d)R^(7d);

R^(2d) is H, alkyl or halo;

R^(3d) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl or cycloalkyl;

R^(5d) is aryl, heteroaryl, arylalkyl or heteroarylalkyl;

R^(6d) and R^(7d) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6d) and R^(7d)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(8d) is H or alkyl.

In another embodiment of Formula IVd, a compound of Formula IVd is acompound wherein

R^(1d) is OR^(3d) or NR^(6d)R^(7d);

R^(2d) is H, alkyl or halo;

R^(3d) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl or cycloalkyl;

R^(5d) is aryl, heteroaryl, arylalkyl or heteroarylalkyl;

R^(6d) and R^(7d) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6d) and R^(7d)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R^(8d) is H or alkyl.

In another embodiment of Formula IVd, a compound of Formula IVd is acompound wherein

R^(1d) is OR^(3d) or NR^(6d)R^(7d);

R^(2d) is H or Br;

R^(3d) is methyl;

R^(5d) is phenyl or as depicted below

wherein phenyl is optionally substituted with one or two substituentseach selected from halogen, methyl, or methoxy;

R^(6d) and R^(7d) are independently selected from hydrogen,pyridinylmethyl, bromophenyl, or as depicted below:

-   -   or R^(6d) and R^(7d) are combined to form a cyclic structure        including the nitrogen atom to which they are both attached, as        shown below

and

R^(8d) is H or cyclopropyl.

In one embodiment, the compound of Formula IVd is:

In another embodiment, the compound of Formula IV is a compound ofFormula IVe:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1e) is aryl or heteroaryl;

R^(2e) is H or alkyl;

R^(5e) is H or alkyl; and

R^(6e) and R^(7e) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6e) and R^(7e)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached.

In another embodiment of Formula IV, a compound of Formula IVe is acompound wherein

R^(1e) is pyridinyl;

R^(2e) is H;

R^(5e) is H or methyl; and

R^(6e) and R^(7e) are independently selected from hydrogen or thesubstituent as depicted below:

In one embodiment, the compound of Formula IVe is:

In another embodiment, the compound of Formula IV is a compound ofFormula IVf:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1f) is H or alkyl;

R^(2f) is aryl, heteroaryl or NR^(6f)R^(7f);

R^(5f) is aryl or heteroaryl;

R^(8f) is H or alkyl;

R^(6f) and R^(7f) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6f) and R^(7f)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached.

In another embodiment of Formula IVf, a compound of Formula IVf is acompound wherein:

R^(1f) is H;

R^(2f) is selected from one of the following:

R^(5f) is phenyl or pyridinyl; and

R^(8f) is H or methyl.

In one embodiment, the compound of Formula IVf is:

In one embodiment, the compound of Formula IV is selected with theproviso that the compound is not

In one embodiment, the compound of Formula IVa is selected with theproviso that the compound is not

In one embodiment, the compound of Formula IV is selected with theproviso that if X is O, then R⁸ is not optionally substitutedmorpholino.

In one embodiment, the compound of Formula IV is selected with theproviso that if X is N-aryl, then R² is not heteroaryl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula V:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸ and R⁹ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NRC(O)R⁴, and NR⁶R⁷; wherein R² and R⁸ are combined to form a cyclicstructure including the carbon atoms to which they are attached in thefive-membered ring;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

X is O, S or NR⁵.

In another embodiment, the compound of Formula V is a compound ofFormula Va:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is H or alkyl;

R^(8a) is aryl, heteroaryl, C(O)R⁴ or S(O)_(p)R⁴;

R^(9a) is OR³, NR⁵C(O)R⁴ or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached; and

p is 0-2.

In another embodiment of Formula V, a compound of Formula Va is acompound wherein

R^(1a) is H;

R^(2a) is H;

R^(8a) is phenyl, C(O)R⁴ or S(O)_(p)R⁴;

wherein phenyl is substituted with halogen;

R^(9a) is OR, NR⁶R⁷, or selected from one of the following

R³ is phenyl,

wherein phenyl is optionally substituted with one or two substituentseach selected from halogen, methoxy and methyl;

R⁴ is selected from the following:

R⁶ and R⁷ are independently selected from ethyl, phenyl, or biphenyl;

R and R′ are H; and

p is 2.

In another embodiment of Formula V, a compound of Formula Va is acompound wherein

R^(1a) is H;

R^(2a) is H;

R^(8a) is phenyl, C(O)R⁴ or S(O)_(p)R⁴;

wherein phenyl is substituted with halogen;

R^(9a) is OR, NR⁶R⁷, or selected from one of the following

R³ is phenyl,

wherein phenyl is optionally substituted with one or two substituentseach selected from halogen, methoxy and methyl;

R⁴ is selected from the following:

R⁶ and R⁷ are independently selected from ethyl, phenyl, or biphenyl;

R and R′ are H; and

p is 2.

In one embodiment, the compound of Formula Va is:

In another embodiment, the compound of Formula V is a compound ofFormula Vb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is H or alkyl;

R^(2b) is H or alkyl;

R^(8b) is C(O)R⁴ or S(O)_(p)R⁴;

R^(9b) is aryl, heteroaryl, halo or C(O)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

X is O or NR⁵; and

p is 0-2.

In another embodiment, Formula Vb is:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is H or alkyl;

R^(2b) is H or alkyl;

R^(8b) is C(O)R⁴ or S(O)_(p)R⁴;

R^(9b) is aryl, heteroaryl, halo or C(O)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

X is O, S or NR⁵; and

p is 0-2.

In another embodiment of Formula Vb, a compound of Formula Vb is acompound wherein

R^(1b) is H, halogen, or COCH₃;

R^(2b) is H, halogen, or COCH₃;

R^(8b) is C(O)R⁴;

R^(9b) is H, halogen, phenyl, or C(O)R⁴;

wherein phenyl is optionally substituted with halogen;

R⁴ is NR⁶R⁷;

R⁶ and R⁷ are independently selected from H, cyclopropyl, thienylmethyl,furanylmethyl, cyclopentyl, methyl, and benzyl;

wherein benzyl is substituted with two methoxy substituents;

X is O, S or NCH₃; and

p is 2.

In one embodiment, the compound of Formula Vb is:

In another embodiment, the compound of Formula V is a compound ofFormula Vc:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1c) is H, alkyl or C(O)R⁴;

R^(2c) is H, alkyl or C(O)R⁴;

R^(8c) is H or alkyl;

R^(9c) is OR³, NR⁵C(O)R⁴ or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

R and R′ are independently selected from hydrogen and alkyl, and R andR′ are combined to form a cyclic structure including the carbon atom towhich they are both attached.

In another embodiment of Formula Vc, a compound of Formula Vc is acompound wherein

R^(1c) is H or C(O)R⁴;

R^(2c) is H or C(O)R⁴;

R^(8c) is H or methyl;

R^(9c) is OR³;

R³ is selected from one of the following:

R⁴ is methyl; and

R and R′ are H.

In one embodiment, the compound of Formula Vc is:

In another embodiment, the compound of Formula V is a compound ofFormula Vd:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1d) is H, alkyl, aryl or heteroaryl;

R^(2d) is C(O)R⁴;

R^(8d) is NR⁵C(O)R⁴ or N═C(R)NR⁶R⁷;

R^(9d) is H, alkyl, arylalkyl or heteroarylalkyl; wherein R^(1d) andR^(9d) are combined to form a cyclic structure including the carbonatoms to which they are attached in the five-membered ring;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

R and R′ are independently selected from hydrogen and alkyl, or R and R′are combined to form a cyclic structure including the carbon atom towhich they are both attached.

In another embodiment of Formula Vd, a compound of Formula Vd is acompound wherein

wherein R^(1d) is H, methyl, or phenyl,

wherein phenyl is optionally substituted with methyl or halogen;

R^(2d) is C(O)R⁴, or as depicted below

R^(8d) is phenyl or NR⁵C(O)R⁴,

wherein phenyl is substituted with propyl;

R^(9d) is H, methyl, benzodioxylphenylmethyl, and wherein R^(1d) andR^(9d) are combined to form a seven-membered cyclic structure includingthe carbon atoms to which they are attached in the five-membered ring;

R⁴ is ethyl, methyl, t-butyl, benzyl or as depicted below

wherein benzyl is optionally substituted with 1-3 substituents eachselected from methoxy

R⁵ is H; and

R and R′ are H.

In another embodiment of Formula Vd, a compound of Formula Vd is acompound wherein

wherein R^(1d) is H, methyl, or phenyl,

wherein phenyl is optionally substituted with methyl or halogen;

R^(2d) is C(O)R⁴, or as depicted below

R^(8d) is phenyl or NR⁵C(O)R⁴,

wherein phenyl is substituted with propyl;

R^(9d) is H, methyl, benzodioxylphenylmethyl, and wherein R^(1d) andR^(9d) are combined to form a seven-membered cyclic structure includingthe carbon atoms to which they are attached in the five-membered ring;

R⁴ is ethyl, methyl, t-butyl, benzyl, p-isopropylphenyl or as depictedbelow

wherein benzyl is optionally substituted with 1-3 substituents eachselected from methoxy

R⁵ is H; and

R and R′ are H.

In one embodiment, the compound of Formula Vd is:

In another embodiment, the compound of Formula V is a compound ofFormula Ve:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1e) is H or alkyl;

R^(2e) is C(O)R⁴;

R^(8e) is H or alkyl;

R^(9e) is H or alkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(5e) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached.

In another embodiment of Formula Ve, a compound of Formula Ve is acompound wherein

R^(1e) is H;

R^(2e) is C(O)R⁴;

R^(8e) is H or alkyl;

R^(9e) is H or alkyl;

R⁴ is selected from the following:

R^(5e) is methoxyethyl, propenyl, or cyclohexenylpropyl.

In one embodiment, the compound of Formula Ve is:

In another embodiment, the compound of Formula V is a compound ofFormula Vf:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1f) is H or alkyl;

R^(2f) is S(O)_(p)R⁴;

R^(8f) is C(O)R⁴;

R^(9f) is aryl, H or alkyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment of Formula Vf, a compound of Formula Vf is acompound wherein

R^(1f) is H;

R^(2f) is S(O)_(p)R⁴;

R^(8f) is C(O)R⁴;

R^(9f) is aryl H or alkyl;

R⁴ is thiomorpholinyl or as depicted below

and

p is 2.

In one embodiment, the compound of Formula Vf is:

In one embodiment, the compound of Formula V is selected with theproviso that the compound is not

In one embodiment, the compound of Formula V is selected with theproviso that if X is S and R⁹ is aryl, then neither R⁸ nor R² ismorpholino.

In one embodiment, the compound of Formula V is selected with theproviso that if X is S and R⁹ is aryl, heteroaryl, oxazolidinonyl,arylcarbonyl, then R⁸ is not morpholino, acyl or an ester.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula VI:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ is independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl,halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

A is a substituted or unsubstituted 5 or 6 membered aryl, heteroaryl,carbocyclic or heterocyclic ring.

In another embodiment, the compound of Formula VI is a compound ofFormula VIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), is aryl or heteroaryl;

R^(8a), is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, orNR⁶R⁷;

R^(9a), is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In one embodiment of Formula VIa, a compound of Formula VIa is acompound wherein

wherein R^(1a) is aryl or heteroaryl;

R^(8a) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(9a) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, orNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment of Formula VIa, a compound of Formula VIa is acompound wherein

R^(1a) is pyridinyl,

wherein pyridinyl is optionally substituted with one or two substituentseach selected from OR³;

R³ is difluoroethyl;

R^(8a) is H, methyl, phenyl, C(O)R⁴;

R^(9a) is H, phenyl, methyl, thienyl, ethyl, furanyl, or butyl, whereinphenyl is optionally substituted with a substituent selected fromhalogen or methoxy;

R⁴ is —NR⁶R⁷; and

R⁶ and R⁷ are independently selected from H, methyl, and ethyl.

In one embodiment, the compound of Formula VIa is:

In another embodiment, the compound of Formula VI is a compound ofFormula VIa1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a1) is aryl, heteroaryl or NR⁶R⁷;

R^(8a1) is H or alkyl;

R^(9a1) is H, alkyl, alkenyl, carbocyclic, halo, pseudohalo,trifluoromethyl, cyano, or C(O)NR⁶R⁷; and

R⁶ and R⁷ are independently selected from H, methyl, and ethyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is aryl, heteroaryl NR⁶R⁷;

R^(8a1) is H, aryl, or alkyl;

R^(9a1) is H, alkyl, alkenyl, halo or pseudohalo; and

R⁶ and R⁷ are independently selected from H, methyl, and ethyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is aryl, heteroaryl or NR⁶R⁷;

R^(8a1) is H or alkyl;

R^(9a1) is alkyl, alkenyl, halo or pseudohalo, wherein the alkyl groupis not CH₃; and

R⁶ and R⁷ are independently selected from H, methyl, and ethyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is pyridinyl or NH₂,

R^(8a1) is H or methyl;

R^(9a1) is H or methyl.

In one embodiment, the compound of Formula VIa1 is:

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is pyridinyl,

R^(8a1) is H or methyl;

R^(9a1) is fluoro, bromo, chloro or iodo.

In one embodiment, the compound of Formula VIa1 is:

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is 2-pyridinyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein R^(1a1) is methoxypyridinyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is 2-pyridyl;

R^(8a1) is H or Ph;

R^(9a1) is carbocyclic, halo, trifluoromethyl, cyano, or C(O)NR⁶R⁷;

R⁶ is H or alkyl;

and R⁷ is alkyl.

In another embodiment of Formula VIa1, a compound of Formula VIa1 is acompound wherein

R^(1a1) is 2-pyridyl;

R^(8a1) is H or methyl;

R^(9a1) is carbocyclic, halo, trifluoromethyl, cyano, or C(O)NR⁶R⁷;

R⁶ is H or alkyl;

and R⁷ is alkyl.

In another embodiment, the compound of Formula VI is a compound ofFormula VIb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is aryl, heteroaryl, S(O)_(p)R⁴, NR⁵C(O)R⁴, or NR⁶R⁷;

R^(8b) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, orNR⁶R⁷;

R^(9b) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷; or R^(8b) and R^(9b) are combined to form a cyclic structureincluding the carbon atoms to which they are attached in thefive-membered ring;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R^(5b) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment of Formula VIb, a compound of Formula VIb is acompound wherein

R^(1b) is pyridinyl, S(O)_(p)R⁴,

R^(8b) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, orNR⁶R⁷;

R^(9b) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷; wherein R^(8b) and R^(9b) are combined to form a cyclic structureincluding the carbon atoms to which they are attached in thefive-membered ring;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is depicted below

R^(5b) is hydrogen or ethyl;

p is 0.

In one embodiment, the compound of Formula VIb is:

In another embodiment, the compound of Formula VIb is a compound ofFormula VIb1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b1) is aryl, heteroaryl, or NR⁶R⁷;

R^(1b1) is H or alkyl;

R^(9b1) is aryl, heteroaryl, heterocyclyl, halo, pseudohalo, C(O)R⁴, orS(O)_(p)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridyl;

R^(8b1) is H or alkyl;

R^(9b1) is substituted phenyl, heteroaryl, heterocyclyl, fluoro, chloro,iodo, C(O)R⁴, or S(O)_(p)R⁴, wherein the heteroaryl group is not asubstituted pyrazole;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl or NH₂;

R^(8b1) is H;

R^(9b1) is aryl, heteroaryl, halo, heterocyclyl or C(O)R⁴;

R⁴ is —NR⁶R⁷; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is 2-pyridyl;

R^(1b1) is H or methyl;

R^(9b1) is substituted phenyl, heteroaryl, heterocyclyl, C(O)NR⁶R⁷,wherein the heteroaryl group is not a substituted pyrazole; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocycloalkyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is 2-pyridyl;

R^(1b1) is H;

R^(9b1) is substituted phenyl, heteroaryl, heterocyclyl, C(O)NR⁶R⁷,wherein the heteroaryl group is not a substituted pyrazole; and

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocycloalkyl,or R⁶ and R⁷ are combined to form a cyclic structure including thenitrogen atom to which they are both attached.

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is NH₂;

R^(8b1) is H;

R^(9b1) is Br,

In another embodiment of Formula VIb1, a compound of Formula VIb11 is acompound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

R^(9b1) is Br,

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein R^(1b1) is 2-pyridyl.

In one embodiment, the compound of Formula VIb1 is:

In one embodiment, the compound of Formula VIb1 is:

In one embodiment, the compound of Formula VIb1 is:

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

R^(9b1) is

In another embodiment of Formula VIb1, a compound of Formula VIb1 is acompound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

R^(9b1) is

In another embodiment, the compound of Formula VI is a compound ofFormula VIc:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1c) is aryl, or heteroaryl; and

R may consist of 0-6 substituents independently selected from H oralkyl.

In another embodiment of Formula VIc, a compound of Formula VIc is acompound wherein

R^(1c) is pyridinyl; and

R is H.

In one embodiment, the compound of Formula VIc is:

In another embodiment, the compound of Formula VI is a compound ofFormula VId:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1d) is aryl or heteroaryl;

R^(5d) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl; and

X is CH or N.

In another embodiment of Formula VId, a compound of Formula VId is acompound wherein

R^(1d) is pyridinyl;

R^(5d) is hydrogen or phenyl,

wherein phenyl is substituted with CF₃;

X is CH or N.

In one embodiment, the compound of Formula VId is:

In another embodiment, the compound of Formula VI is a compound ofFormula VIe:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1e) is S(O)_(p)R⁴, NR⁵C(O)R⁴ or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(5e) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

R may consist of 0-4 subsituents independently selected from H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, or NR⁶R⁷.

In another embodiment, the compound of Formula VI is a compound ofFormula VIe:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1e) is S(O)_(p)R⁴ or NR⁶R⁷;

R⁴ is

R^(5e) is H, methoxyethyl or CH₃OCH₂(CH₃)CH—;

R⁶ and R⁷ are independently selected from hydrogen or as depicted below

p is 0; and

R is H or halogen.

In one embodiment, the compound of Formula VIe is:

In another embodiment, the compound of Formula VI is a compound ofFormula VIf:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1f) is aryl, or heteroaryl; and

R^(2f) is H, —C(O)R, —C(O)OR, —S(O)₂R, —S(O)R or alkyl,

wherein R is aryl, heteroaryl or alkyl.

In another embodiment of Formula VIf, a compound of Formula VIf is acompound wherein

R^(1f) is 2-pyridyl; and

R^(2f) is —C(O)R, —C(O)OR or SO₂R,

wherein R is aryl, heteroaryl or alkyl.

In another embodiment of Formula VIf, a compound of Formula VIf is acompound wherein

R^(1f) is 2-pyridyl; and

R^(2f) is —C(O)R,

wherein R is aryl, heteroaryl or alkyl.

In another embodiment of Formula VIf, a compound of Formula VIf is acompound wherein

R^(1f) is pyridinyl; and

R^(2f) is H

In one embodiment, the compound of Formula VIf is:

In another embodiment, the compound of Formula VI is a compound ofFormula VIg:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1g) is aryl or heteroaryl; and

R^(5g) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl.

In another embodiment of Formula VIg, a compound of Formula VIg is acompound wherein

R^(1g) is 2-pyridyl; and

R^(5g) is aryl, heteroaryl, heterocyclyl, cycloalkyl, CH₂C(O)R, whereinR is NH₂, NHalkyl, N(alkyl)₂, piperidine, OH or Oalkyl.

In another embodiment of Formula VIg, a compound of Formula VIg is acompound wherein

R^(1g) is pyridinyl; and

R^(5g) is hydrogen, phenyl, pyridyl or

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula VII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2.

In another embodiment, the compound of Formula VII is a compound ofFormula VIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is aryl or heteroaryl;

R^(2a) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, andNR⁶R⁷;

R^(8a) is H or alkyl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2.

In another embodiment of Formula VIIa, a compound of Formula VIIa is acompound wherein

R^(1a) is pyridinyl;

R^(2a) is selected from one of the following:

and

R^(8a) is methyl.

In another embodiment of Formula VIIa, a compound of Formula VIIa is acompound wherein

R^(1a) is pyridinyl;

R^(2a) is selected from one of the following:

and

R^(8a) is methyl.

In one embodiment, the compound of Formula VIIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula VIIa or Formula VIIb:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, is independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl,halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

A is a substituted or unsubstituted 5 or 6 membered aryl, heteroaryl,carbocyclic or heterocyclic ring.

In another embodiment, the compound of Formula VIIIa is a compound ofFormula VIIIa1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a1) is H, aryl or heteroaryl;

R^(2a1) is H, alkyl, alkoxy or aryloxy;

R^(8a1) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, orNR⁶R⁷;

R^(9a1) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, orNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(5a1) is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment of Formula VIIIa1, a compound of Formula VIIIa1 isa compound wherein

R^(1a1) is H;

R^(2a1) is H;

R^(8a1) is phenyl,

wherein phenyl is substituted with methoxy;

R^(9a1) is phenyl,

wherein phenyl is substituted with methoxy;

R^(5a1) is depicted below:

In one embodiment, the compound of Formula VIIIa1 is:

In another embodiment, the compound of Formula VIIIb is a compound ofFormula VIIIb1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b1) is H, alkyl, aryl or heteroaryl;

R^(8b1) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, orNR⁶R⁷;

R^(9b1) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, orNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R^(6b1) and R^(7b1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6b1) andR^(7b1) are combined to form a cyclic structure including the nitrogenatom to which they are both attached; and

p is 0-2.

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb1 isa compound wherein

R^(1b1) is 2-pyridyl;

R^(8b1) is H, methyl or phenyl;

R^(9b1) is H, alkyl, alkenyl, alkynyl, substituted aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NRC(O)R⁴, or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R^(6b1) and R^(7b1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R^(6b1) and R^(7b1) are combinedto form a cyclic structure including the nitrogen atom to which they areboth attached; and

wherein NR^(6b1)R^(7b1) is not NHMe, NHEt, NHn-Pr, NHbenzyl orNH-2-phenethyl; and

wherein NR^(6b1)R^(7b1) is not morpholine when R^(8b1) and R^(9b1) areboth hydrogen; and

p is 0-2.

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb1 isa compound wherein

R^(1b1) is 2-pyridyl;

R^(1b1) is H;

R^(9b1) is substituted aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,C(O)NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R^(6b1) and R^(7b1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R^(6b1) and R^(7bl) are combinedto form a cyclic structure including the nitrogen atom to which they areboth attached; and

wherein NR^(6b1)R^(7b1) is not NHMe, NHEt, NHn-Pr, NHCH₂CH₂OH, NHbenzyloptionally substituted on the phenyl ring, or NH-2-phenethyl optionallysubstituted on the phenyl ring; and

wherein NR^(6b1)R^(7b1) is not morpholine when R^(8b1) and R^(9b1) areboth hydrogen.

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb1 isa compound wherein

R^(1b1) is H, methyl, or pyridinyl;

R^(8b1) is H or methyl;

R^(9b1) is H or phenyl,

wherein phenyl is optionally substituted with one or two substituentsselected from methoxy;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R^(6b1) land R^(7b1) are independently selected from H, methyl,hydroxypropyl, methoxypropyl, hydroxyethyl, morpholinylethyl,furanylmethyl, or one of the following:

R^(6b1) land R^(7b1) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached, as depicted below

In one embodiment, the compound of Formula VIIIb1 is:

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb1 isa compound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H, methyl or phenyl;

R^(9b1) is H, bromo or phenyl; and

NR^(6b1)R^(7b1) is selected from

wherein NR^(6b1)R^(7b1) is not morpholine when R^(8b1) and R^(9b1) areboth hydrogen.

In one embodiment, the compound of Formula VIIIb1 is:

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb1 isa compound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H, methyl or phenyl;

R^(9b1) is —C(O)NR⁶R⁷; and is selected from

NR^(6b1)R^(7b1) is selected from

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb1 isa compound wherein

R^(1b1) is pyridinyl;

R^(8b1) is H;

R^(9b1) is H;

R^(6b1) and R^(7b1) are independently selected from H,

In one embodiment, the compound of Formula VIIIb1 is:

In another embodiment of Formula VIIIb1, a compound of Formula VIIIb1 isa compound wherein

R^(1b1) is pyridinyl or methoxypyridinyl;

R^(8b1) is H;

R^(9b1) is H, bromo, chloro, cyano, trifluoromethyl or phenyl; and

NR^(6b1)R^(7b1) is

In one embodiment, the compound of Formula VIIIb1 is:

In another embodiment, the compound of Formula VIIIb is a compound ofFormula VIIIb2:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b2) is H, aryl or heteroaryl;

R^(6b2) and R^(7b2) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6b2) andR^(7b2) are combined to form a cyclic structure including the nitrogenatom to which they are both attached;

p is 0-2; and

R may consist of 0-6 subsituents independently selected from H or alkyl.

In another embodiment, the compound of Formula VIIIb is a compoundwherein

R^(1b2) is pyridinyl;

R^(6b2) and R^(7b2) are independently selected from one of thefollowing:

R^(6b2) and R^(7b2) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached, as depicted below:

R is H.

In one embodiment, the compound of Formula VIIIb2 is:

In another embodiment, the compound of Formula VIIIb is a compound ofFormula VIIIb3:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b3) is H, aryl or heteroaryl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R^(6b3) and R^(7b3) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6b3) andR^(7b3) are combined to form a cyclic structure including the nitrogenatom to which they are both attached;

p is 0-2; and

R may consist of 0-4 subsituents independently selected from H, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, or NR⁶R⁷.

In another embodiment, the compound of Formula VIIIb3 is a compoundwherein:

R^(1b3) is thienyl;

R^(6b3) and R^(7b3) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached, as depicted below

and

R is H.

In one embodiment, the compound of Formula VIIIb3 is:

In another embodiment, the compound of Formula VIIIb is a compound ofFormula VIIIb4:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b4) is H, alkyl, aryl or heteroaryl;

R^(8b4) is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, orNR⁶R⁷;

R^(9b4) is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, C(O)R⁴, or S(O)_(p)R⁴;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

each R⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R^(6b4) and R^(7b4) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6b4) andR^(7b4) are combined to form a cyclic structure including the nitrogenatom to which they are both attached; and

p is 0-2.

In one embodiment of Formula VIIIb4, a compound of Formula VIIIb4 is acompound wherein

wherein R^(1b4) is 2-pyridyl;

R^(8b4) is H;

R^(9b4) is CH₂CONHR, wherein R is H, alkyl, aryl, arylakyl, heteroaryl;

NR^(6b4)R^(7b4) is a morpholine ring; and

p is 0-2.

In one embodiment of Formula VIIIb4, a compound of Formula VIIIb4 is acompound wherein

R^(1b4) is pyridinyl;

R^(8b4) is H;

R^(9b4) is CH₂CONHR, wherein R is H,

NR^(6b4)R^(7b4) is

In one embodiment, the compound of formula VIIIb is selected with theproviso that if A is a substituted or unsubstituted phenyl or thienylring, and R⁶ is H; then R⁷ is not 4-pyridyl, pyrimidinyl,chloropyridinyl or indazole.

In one embodiment, the compound of formula VIIIb1 is selected with theproviso that if R⁶ is H; then R⁷ is not 4-pyridyl, pyrimidinyl,chloropyridinyl or indazole.

In one embodiment, the compound of formula VIIIb3 is selected with theproviso that if R⁶ is H; then R⁷ is not 4-pyridyl, pyrimidinyl,chloropyridinyl or indazole.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula IXa or Formula IXb:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment, the compound of Formula IXa is a compound ofFormula IXa1.

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a1) is aryl or heteroaryl;

R^(2a1) is H or alkyl;

R^(8a1) is alkyl;

R^(6a1) and R^(7a1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, arylamino, alkylamino,arylcarbonylamino, heteroarylcarbonylamino and alkylcarbonylamino; orR^(6a1) and R^(7a1) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached.

In one embodiment of Formula IXa1, R^(1a1) is aryl or heteroaryl;

R^(2a1) is H or alkyl;

R^(8a1) is alkyl;

R^(6a1) and R^(7a1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, arylamino, alkylamino,arylcarbonylamino, heteroarylcarbonylamino and alkylcarbonylamino; orR^(6a1) and R^(7a1) are combined to form a cyclic structure includingthe nitrogen atom to which they are both attached.

In one embodiment of Formula IXa1, R^(1a1) is 2-pyridyl;

R^(2a1) is H or alkyl;

R^(8a1) is alkyl;

R^(6a1) and R^(7a1) are independently selected from hydrogen, C(O)R,wherein R is alkyl, cycloalkyl, or heterocycloalkyl.

In one embodiment, R^(1a1) is;

R^(2a1) is H or methyl;

R^(8a1) is methyl, ethyl, or trifluoromethyl;

R^(6a1) and R^(7a1) are independently selected from H,

or; or R^(6a1) and R^(7a1) are combined to form

including the nitrogen atom to which they are both attached.

In one embodiment of Formula IXa1, R^(1a1) is

R^(2a1) is H or methyl;

R^(8a1) is H;

R^(6a1) and R^(7a1) are independently selected from H,

In one embodiment, the compound of Formula IXa1 is:

In one embodiment, the compound of Formula IXa1 is:

In another embodiment, the compound of Formula IXb is a compound ofFormula IXb1:

or pharmaceutically acceptable derivatives thereof,

wherein each R^(5b1) is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,or arylcarbonyl;

R^(6b1) and R^(7b1) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached.

In one embodiment, each R^(5b1) is methyl or

R^(6b1) land R^(7b1) are combined to form a piperidine structureincluding the nitrogen atom to which they are both attached.

In one embodiment, the compound of Formula IXb1 is:

In one embodiment, the compound of Formula IXa is selected with theproviso that if R¹ is heteroaryl, then NR⁶R⁷ is not morpholino.

In one embodiment, the compound of Formula IXa1 is selected with theproviso that if R^(1a) is heteroaryl, then NR^(6a)R^(7a) is notmorpholino.

In one embodiment, the compound of Formula IXa is selected with theproviso that if R¹ is morpholino, then NR⁶R⁷ is not NH₂.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula X:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and Rare combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment, the compound of Formula X is a compound ofFormula Xa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is H or halo;

R^(8a) is H or alkyl;

R^(6a) and R^(7a) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6a) and R^(7a)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached.

In one embodiment, R^(1a) is H, methyl, or trifluoromethyl;

R^(2a) is H or Br;

R^(8a) is H, methyl, or trifluoromethyl;

R^(6a) and R^(7a) are independently selected from hydrogen,

or R^(6a) and R^(7a) are combined to form

including the nitrogen atom to which they are both attached.

In one embodiment, the compound of Formula Xa is:

In one embodiment, the compound of Formula X is selected with theproviso that if R¹ is methyl and NR⁶R⁷ is NH₂, then R⁸ is not aryl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XI:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ and R² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and Rare combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment, the compound of Formula XI is a compound ofFormula XIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is C(O)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(5a) is H, aryl or heteroaryl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached.

In one embodiment R^(1a) is H or methyl;

R^(2a1) is

and

R^(5a) is Ph.

In one embodiment, the compound of Formula XIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸ and R⁹ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment, the compound of Formula XII is a compound ofFormula XIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is alkyl or NR⁶R⁷;

R^(2a) is H or alkyl;

R^(8a) is H or alkyl;

R^(9a) is H or R^(6′)R^(7′)NC(O)alkyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

R^(6′) and R^(7′) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl and cycloalkyl; orR^(6′) and R^(7′) are combined to form a cyclic structure including thenitrogen atom to which they are both attached.

In one embodiment, R^(1a) is methyl,

R^(2a) is H;

R^(8a) is methyl or trifluoromethyl; and

R^(9a) is H,

In one embodiment, the compound of Formula XIIa is:

In one embodiment, the compound of Formula XII is selected with theproviso that the compound is not

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XIII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R¹, R⁹, R¹⁰ and R¹¹ are independently selected from thegroup consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and Rare combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment, the compound of Formula XIII is a compound ofFormula XIIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is H or alkyl;

R^(8a) is H or alkyl;

R^(9a) is H or alkyl;

R^(10a) is aryl, heteroaryl or C(O)R⁴;

R^(11a) is H, -alkylOR³ or C(O)R⁴;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and Rare combined to form acyclic structure including the nitrogen atom to which they are bothattached.

In another embodiment, R^(1a) is H or alkyl;

R^(2a) is H, OR^(3a) or alkyl;

R^(8a) is H or alkyl;

R^(9a) is H or alkyl;

R^(10a) is aryl, heteroaryl or C(O)R⁴;

R^(11a) is H, -alkylOR³ or C(O)R⁴;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached.

In one embodiment, R^(1a) is H;

R^(2a) is H or

R^(8a) is H;

R^(9a) is H;

R^(10a) is

and

R^(11a) is H,

In one embodiment, the compound of Formula XIIIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XIV:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸, R⁹ and R¹⁰ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

X is S or NR⁵.

In another embodiment, the compound of Formula XIV is a compound ofFormula XIVa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(8a) and R^(9a) are independently selected from thegroup consisting of H, alkyl or halo;

R^(2a) is H, alkyl, halo, C(O)R⁴ and S(O)_(p)R⁴;

R^(10a) is heterocyclyl, -alkylNR⁶R⁷ or NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

X is S or NR⁵.

In one embodiment, R^(1a), R^(8a) and R^(9a) are H;

R^(2a) is H or

R^(10a) is

R⁵ is H methyl, n-propyl,

and

X is S or NR⁵.

In one embodiment, R^(1a), R^(8a) and R^(9a) are H;

R^(2a) is H, —CO(O)Et, or

R^(10a) is

R⁵ is H, methyl, n-propyl,

and

X is S or NR⁵.

In one embodiment, the compound of Formula XIVa is:

In another embodiment, the compound of Formula XIVa is:

In one embodiment, the compound of formula XIV is selected with theproviso that R¹⁰ is not morpholinomethyl, piperidinylmethyl,methylpiperizinylmethyl, morpholino-CH(CH₃)—, piperidinyl-CH(CH₃)—,methylpiperizinyl-CH(CH₃)—; and X is not NR⁵ if R⁵ is aryloxyalkyl orarylalkyl.

In another embodiment, the disease to be treated with the compounds offormula XIV is not a retinal tumor.

In one embodiment, the compound of formula XIVa is selected with theproviso that R^(10a) is not morpholinomethyl, piperidinylmethyl,methylpiperizinylmethyl, morpholino-CH(CH₃)—, piperidinyl-CH(CH₃)—,methylpiperizinyl-CH(CH₃)—; and X is not NR⁵ if R⁵ is aryloxyalkyl orarylalkyl.

In another embodiment, the disease to be treated with the compounds offormula XIVa is not a retinal tumor.

In one embodiment, the compound of Formula XIV is selected with theproviso that the compound is not

In one embodiment, the compound of Formula XIVa is selected with theproviso that the compound is not

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XVa or Formula XVb:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ is independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl,halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl orheteroarylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and Rare combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

Ar is aryl or heteroaryl.

In another embodiment, the compound of Formula XVa is a compound ofFormula XVa1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H, aryl or heteroaryl; and

R^(5a) is alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl orheteroarylcarbonyl.

In one embodiment, R^(1a) is H, phenyl; and

R^(5a) is

In one embodiment, the compound of Formula XVa1 is

In another embodiment, the compound of Formula XVb is a compound ofFormula XVb1:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H, aryl or heteroaryl;

R^(5a) is alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl orheteroarylcarbonyl; and

Ar is aryl or heteroaryl.

In one embodiment, R^(1a) is

R^(5a) is

and

Ar is

In one embodiment, the compound of Formula XVb1 is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XVI:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸ and R⁹ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2;

each R and R′ are independently selected from H, alkyl, or cycloalkyl;and

Ar is aryl or heteroaryl.

In another embodiment, the compound of Formula XVI is a compound ofFormula XVIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a), R^(8a) and R^(9a) are independently selectedfrom the group consisting of H, alkyl and halo;

R^(5a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl;

R^(6a) and R^(7a) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6a) and R^(7a)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

p is 0-2;

each R and R′ are independently selected from H, alkyl, or cycloalkyl;and

Ar is aryl or heteroaryl.

In one embodiment, R^(1a), R^(2a), R^(8a) and R^(9a) are independentlyselected from the group consisting of H, and F;

R^(5a) is cyclopropyl or

each R and R′ are H or methyl; and

Ar is

In one embodiment, the compound of Formula XVIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XVII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R¹, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, halo, pseudohalo,OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment, the compound of Formula XVII is a compound ofFormula XVIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a), R^(8a), R^(9a), R^(10a), R^(12a), R^(13a),R^(14a) and R^(15a) are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, andNR⁶R⁷;

R^(11a) is NR^(6a)R^(7a);

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

R^(6′) is arylalkyl or heteroarylalkyl;

R^(7′) is H or alkyl, and R⁶ and R⁷ are combined to form a cyclicstructure including the nitrogen atom to which they are both attached;and

p is 0-2.

In one embodiment, R^(1a), R^(2a), R^(8a), R^(9a), R^(10a), R^(12a),R^(13a), R^(14a) and R^(15a) are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R^(11a) is NR^(6a)R^(7a);

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

R⁶ is arylalkyl or heteroarylalkyl;

R⁷ is H or alkyl, and R⁶ and R⁷ are combined to form a cyclic structureincluding the nitrogen atom to which they are both attached; and

p is 0-2.

In one embodiment, wherein R^(1a), R^(2a), R^(8a), R^(9a), R^(10a),R^(12a), R^(13a), R^(14a) and R^(15a) are independently selected fromthe group consisting of H, methyl, F, trifluoromethyl, or OEt; and

R^(11a) is

In one embodiment, the compound of Formula XVIIa is:

In another embodiment, the compound of Formula XVII is a compound ofFormula XVIIb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a), R^(8a), R^(9a), R^(10a) are independentlyselected from the group consisting of H, alkyl, halo, and OR³;

R^(11a), R^(12a), R^(13a), R^(14a) and R^(15a) are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴,S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

R^(6′) is arylalkyl or heteroarylalkyl;

R^(7′) is H or alkyl, and R⁶ and R⁷ are combined to form a cyclicstructure including the nitrogen atom to which they are both attached;and

p is 0-2.

In one embodiment, R^(1b), R^(2b), R^(8b), R^(9b), R^(10b) areindependently selected from the group consisting of H, alkyl, halo, andOR³;

R^(11b), R^(12b), R^(13b), R^(14b) and R^(15b) are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴,S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

R⁶ is arylalkyl or heteroarylalkyl;

R⁷ is H or alkyl, and R⁶ and R⁷ are combined to form a cyclic structureincluding the nitrogen atom to which they are both attached; and

p is 0-2.

In one embodiment, wherein R^(1a), R^(2a), R^(8a), R^(9a), R^(10a) areindependently selected from the group consisting of H, F, OMe, OPh, CF₃,and

and

R^(11a), R^(12a), R^(13a), R^(14a) and R^(15a) are independentlyselected from the group consisting

In one embodiment, wherein R^(1b), R^(2b), R^(8b), R^(9b), R^(10b) areindependently selected from the group consisting of H, F, OMe, OPh, CF₃,and

and

R^(11b), R^(12b), R^(13b), R^(14b) and R^(15b) are independentlyselected from the group consisting

In one embodiment, the compound of Formula XVIIb is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XVIII.

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R¹, R⁹ and R¹⁰ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

X is S(O)_(p) or CR₂, wherein each R is independently selected fromhydrogen and lower alkyl.

In another embodiment, the compound of Formula XVIII is a compound ofFormula XVIIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a), R^(8a), R^(9a) and R^(10a) are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclyl, heteroaryl, nitro, halo, pseudohalo, OR³,C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R^(6a) and R^(7a) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6a) and R^(7a)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached; and

p is 0-2.

In one embodiment, R^(1a), R^(2a), R^(8a), R^(9a) and R^(10a) areindependently selected from the group consisting of H, CH₃, Cl, CF₃,NO₂, OCH₃,

R⁶ and R⁷ are independently selected from hydrogen, CH₃, CH₂CH₃cyclopropyl,

and R⁶ and R⁷ are combined to form

including the nitrogen atom to which they are both attached.

In one embodiment, R^(1a), R^(2a), R^(1a), R^(9a) and R^(10a) areindependently selected from the group consisting of H, CH₃, Cl, CF₃,NO₂, OCH₃,

R^(6a) and R^(7a) are independently selected from hydrogen, CH₃, CH₂CH₃cyclopropyl,

and R^(6a) and R^(7a) are combined to form

including the nitrogen atom to which they are both attached.

In one embodiment, the compound of Formula XVIIIa is:

In another embodiment, the compound of Formula XVIII is a compound ofFormula XVIIIb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b), R^(2b), R^(8a), R^(9b) and R^(10b) are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclyl, heteroaryl, nitro, halo, pseudohalo, OR³,C(O)R⁴, S(O)_(p)R⁴, NRC(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R^(6b) and R^(7b) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6a) and R^(7a)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R and R′ are independently selected from hydrogen and lower alkyl; and

p is 0-2.

In another embodiment, R^(1b), R^(2b), R^(8b), R^(9b) and R^(10b) areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, nitro, halo,pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R^(6b) and R^(7b) are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl, or R^(6a) and R^(7a)are combined to form a cyclic structure including the nitrogen atom towhich they are both attached;

R and R′ are independently selected from hydrogen and lower alkyl; and

p is 0-2.

In one embodiment, R^(1b), R^(2b), R, R^(9b) and R^(10b) areindependently selected from the group consisting of H, OCH₃, SCF₃;

R^(6b) and R^(7b) are independently selected from CH₃ and

and

R and R′ are H.

In another embodiment, R^(1b), R^(2b), R^(8b), R^(9b) and R^(10b) areindependently selected from the group consisting of H, OCH₃, SCF₃;

R^(6b) and R^(7b) are independently selected from CH₃ and

and

R and R′ are H.

In one embodiment, the compound of Formula XVIIIb is:

In one embodiment, the compound of Formula XVIII is selected with theproviso that if X is CH₂, then NR⁶R⁷ is not indolinone orbenzoimidazolone.

In one embodiment, the compound of Formula XVIIIb is selected with theproviso that if R and R′ are both H, then NR⁶R⁷ is not indolinone orbenzoimidazolone.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XIX:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R², R⁸ and R⁹ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, oxo, OR³, C(O)R⁴,S(O)_(p)R⁴, NR⁵C(O)R⁴, and NR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl orarylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment, the compound of Formula XIX is a compound ofFormula XIXa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a), R^(8a) and R^(9a) are independently selectedfrom the group consisting of H, alkyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, oxo and C(O)R⁴;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R^(5a) is alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl,heterocyclylcarbonyl, heteroarylcarbonyl or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, arylcarbonyl or heteroarylcarbonyl, or R⁶ and R⁷ arecombined to form a cyclic structure including the nitrogen atom to whichthey are both attached; and

p is 0-2.

In one embodiment, R^(1a), R^(2a), R^(8a) and R^(9a) are independentlyselected from the group consisting of H, cyclopentyl, cyclohexyl, NO₂,

and

R^(5a) is

In another embodiment, R^(1a), R^(2a), R^(8a) and R^(9a) areindependently selected from the group consisting of H, cyclopentyl,cyclohexyl, oxo

and

R^(5a) is

In one embodiment, the compound of Formula XIXa is:

In one embodiment, the compound of formula XIX is selected with theproviso that the compound does not contain a hydrazide, a macrocycle, athienopyridine or a thienopyrimidine.

In another embodiment, the disease to be treated with the compounds offormula XIX is not hepatocellular cancer.

In one embodiment, the compound of formula XIXa is selected with theproviso that the compound does not contain a hydrazide, a macrocycle, athienopyridine or a thienopyrimidine.

In another embodiment, the disease to be treated with the compounds offormula XIXa is not hepatocellular cancer.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XX:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ and R² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

p is 0-2.

In another embodiment, the compound of Formula XX is a compound ofFormula XXa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is OR³, S(O)_(p)R⁴, NR⁵C(O)R⁴ or NR⁶R⁷;

R^(2a) is alkyl, aryl or heteroaryl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

R and R′ are independently selected from hydrogen and lower alkyl; and

p is 0-2.

In one embodiment, R^(1a) is CH₃, Bn,

R² is CH₃, CH₂CH₃, t-Bu, Ph,

and

R and R′ are independently selected from hydrogen and CH₃.

In one embodiment, the compound of Formula XXa is:

In another embodiment, the compound of Formula XX is a compound ofFormula XXb:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is alkyl, arylalkyl or heteroarylalkyl;

R^(2b) is aryl, heteroaryl, or C(R)(R′)NR⁶R⁷;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached; and

R and R′ are independently selected from hydrogen and lower alkyl.

In one embodiment, R^(1b) is CH₃,

and

R^(2b) is

In one embodiment, the compound of Formula XXb is:

In another embodiment, the compound of Formula XX is a compound ofFormula XXc:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1b) is aryl or heteroaryl; and

R^(2b) is heterocyclyl.

In one embodiment, R^(1b) is

and

R^(2b) is

In one embodiment, the compound of Formula XXc is:

In one embodiment, the compound of Formula XX is selected with theproviso that if R¹ is pyridyl, then R² is not phenyl.

In one embodiment, the compound of Formula XX is selected with theproviso that if R² is pyridyl, then R¹ is not phenyl or cyclohexyl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XXI:

or pharmaceutically acceptable derivatives thereof,

wherein R¹, R² and R⁸ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴,NR⁵C(O)R⁴, and NR⁶R⁷;

R⁹ is H or alkyl;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

p is 0-2; and

Ar is aryl or heteroaryl.

In another embodiment, the compound of Formula XXI is a compound ofFormula XXIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a), R^(2a) and R^(8a) are H or alkyl;

R^(9a) is H or alkyl;

R^(5a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, orarylcarbonyl; and

Ar is aryl or heteroaryl.

In one embodiment, R^(1a), R^(2a) and R^(8a) are H;

R⁹ is H or CH₃;

R^(5a) is Bn,

and

Ar is Ph,

In one embodiment, the compound of Formula XXIa is:

In one embodiment, the compound of Formula XXI is selected with theproviso that if Ar is pyridyl, then R⁵ is not phenyl.

In one embodiment, the compound of Formula XXIa is selected with theproviso that if Ar is pyridyl, then R⁵ is not phenyl.

In certain embodiments, the compounds for use in the compositions andmethods provided herein are of Formula XXII:

or pharmaceutically acceptable derivatives thereof,

wherein R¹ and R² are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,heteroaryl, halo, pseudohalo, OR³, C(O)R⁴, S(O)_(p)R⁴, NR⁵C(O)R⁴, andNR⁶R⁷;

R³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl or arylcarbonyl;

R⁴ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy,alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy,aralkoxy, or —NR⁶R⁷;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, or arylcarbonyl;

R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl,cycloalkylcarbonyl, or arylcarbonyl, or R⁶ and R⁷ are combined to form acyclic structure including the nitrogen atom to which they are bothattached;

n is 0 or 1;

p is 0-2; and

each Ar is independently selected from aryl or heteroaryl.

In another embodiment, the compound of Formula XXII is a compound ofFormula XXIIa:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is H;

n is 0 or 1; and

each Ar is independently selected from aryl or heteroaryl.

In another embodiment, Formula XXIIa is:

or pharmaceutically acceptable derivatives thereof,

wherein R^(1a) is H or alkyl;

R^(2a) is H;

n is 0 or 1; and

each Ar is independently selected from aryl or heteroaryl.

In one embodiment, R^(1a) is H or CH₃;

R^(2a) is H;

n is 0 or 1; and

Ar is independently selected from Ph,

In one embodiment, R^(1a) is H or —CH₃;

R^(2a) is H;

n is 0 or 1; and

Ar is independently selected from

In one embodiment, the compound of Formula XXIIa is:

In certain embodiments, the compounds for use in the compositions andmethods provided herein are selected from the group consisting of thefollowing:

5. SYNTHESIS OF THE COMPOUNDS

The compounds provided herein may be obtained from commercial sources orreadily synthesized by methods well known to those of skill in the art.

5.1 Synthetic Procedures

Amide

A vial was charged with 0.6 mmol of Reagent B, 1.6 mmol of DIPEA, anddry acetonitrile (1 mL). To the stirred reaction mixture 0.5 mmol ofReagent A (in case of amine salt, an additional 1.5 equivalent amount ofDIPEA was added to the reaction mixture), and 0.72 mmol of2-chloro-N-methylpyridinium iodide was added. The reaction vial wasplaced into a water bath and left at 100° C. for 6 hrs. Reaction mixturewas cooled to room temperature and diluted by 6 mL of water. Then thevial was sonicated. If crystalline precipitate was formed it wasfiltered off. In case an oily product was formed the vial was leftovernight, then the water layer was removed and 2-propanol (1 mL) wasadded to cause the crystallization. The precipitate was filtered, washedtwice with a sodium carbonate solution, and then washed with methanol.Purification of the final compounds was performed via preparative HPLCon Agilent 1260 Infinity systems equipped with DAD and mass-detectors.Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm withSunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10 mm was used.Solvents used were deionized Water (phase A) and HPLC-grade Methanol(phase B). Preset chromatography gradient methods were chosen on thebasis of compound properties.

A vial was charged with 0.6 mmol of Reagent B, a solvent (1 mL of asolution of 200 g HOBt in 1 L of DMF), 0.57 mmol of Reagent A (in caseof using amine salt, an additional 1.5 equivalent amount of DIPEA wasadded to the reaction mixture to transfer the amine to base form) and0.66 mmol of EDC. In case the reaction mixture becomes highly viscous0.5 mL of DMF were added. In case the reaction mixture was a homogeneousthe it was kept at room temperature for 72 hrs. Otherwise the reactionmixture was sonicated at room temperature for 5 days. Reaction mixturewas diluted with 6 mL of 1% sodium phosphate water solution. Then thevial was sonicated. In case a crystalline precipitate was formed it wasfiltered off. In case an oily product was formed the product wasdissolved in methanol and precipitated by an addition of 4% hydrochloricacid. Alternatively 2-propanol (1 mL) was mixed with the crude productand the mixture was sonicated. Then the solution was diluted with 5%aqueous sodium hydrogen carbonate (the procedure repeated 2-3 times ifnecessary). Purification of the compounds was performed via preparativeHPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

A vial was charged with 0.57 mmol of Reagent B and dry DMF (1 mL). Tothe stirred reaction mixture 0.57 mmol of N,N-carbodiimidazole wasadded. After 1 hr of stirring the vial was open and the reaction mixturewas left for 2 hrs in a drying oven at 60° C. Then 0.52 mmol of ReagentA (in case of amine salt, an additional 1.5 equivalent amount of DIPEAwas added to the reaction mixture) was added, the vial was firmlyclosed, and the reaction mixture was stirred. The reaction vial wasplaced into a water bath and left at 100° C. for a time specified on thevial label. Reaction mixture was cooled to room temperature and waterwas added until the vial was full. Then the vial was sonicated. In casea crystalline precipitate was formed the vial was passed to thefiltration. In case an oily product was formed the vial was leftovernight, then the water layer was removed and 2-propanol (1 mL) wasadded to cause the crystallization. The precipitate was filtered, washedtwice with a sodium carbonate solution, and then washed with awater/2-propanol (1:1) solution. Purification of the compounds wasperformed via preparative HPLC on Agilent 1260 Infinity systems equippedwith DAD and mass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å,5 μm, 19 mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm,19 mm×10 mm was used. Solvents used were deionized Water (phase A) andHPLC-grade Methanol (phase B). Preset chromatography gradient methodswere chosen on the basis of compound properties.

In a large vial 1.2 mmol of a Reagent B was loaded, then 1 mmol of aReagent A (in case of amine salt, an additional 1.5 equivalent amount ofDIPEA was added to the reaction mixture) and polymeric EDC (3 mmol, MW833 g/mol) were added. 10 ml of solvent (30 g of pentaflourophenol in 1L of dichloromethane) were added, the vial was closed and mixture wasstirred. The vial was shaked continuously for 72 hours using shaker.Reaction mixture was filtered, collecting filtrate in a big tared vial.Precipitated polymer was preserved. Filtrate was evaporated, residue wasweighed. If amount of the residue was low, then a small portion ofmethanol (about 5 ml) was added to the precipitated polymer and shakedfor 4 hours. Methanol solution was filtered to the vial with driedresidue after the first filtration. Filtrate was evaporated again andthe residue was passed to the chromatography. Purification of thecompounds was performed via preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Oxadiazole Synthesis

0.6 mmol of Reagent B was loaded into a small vial. 0.6 mL of solvent (asolution of 200 g N-oxybenzotriazole in 1 L of DMF) and 0.6 mmol ofReagent A (in case of amine salt, an additional 1.5 equivalent amount ofDIPEA was added to the reaction mixture) were added to it. 0.9 mmol ofEDC was added to the reactionary mixture after this. If the reactionarymixture was homogeneous it should be kept at the room temperature for 72hours. If not, it should be sonicated for 5 days at the room temperaturewithout any serious heating. 0.6 mmol of TEA was added after this andthe vial with the reactionary mixture was put into bain-marie and heatedat 100 C for a time indicated on the vial label (ca. 3 h). Thereactionary mixture was cooled than and 3 mL of CH₂CL2 with water inamount enough to fill the vial was added to it. The organic layer waswashed out with water two times. All water was removed after this andthe product was forwarded for the further drying. Purification of thecompounds was performed via preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

1.6 mmol of Reagent A was loaded in small vial then 2 ml of ethanol, 2.4mmol of hydroxylamine and 3.2 mmol of TEA were added. If the reactionmixture is not homogenous then another portion of ethanol (1 mL) wasadded, stirred for 3-4 hours on shaker and left at rt overnight. Then itwas heated at 80° C. for 3 hours and the solvent was removed underreduced pressure. The solid residue was dissolved in 1 mL of solvent (1mL of a solution of 200 g HOBt in 1 L of DMF), 1.6 mmol of Reagent B and2.4 mmol of CDI and sonicated for 3 days at rt. In case the reactionmixture was viscous additional 1 mL of DMF was added. Then 1.6 mmol ofTEA were added and the vial was heated at 100° C. for 3 hours. Thereaction mixture was cooled, diluted with 3 ml of water and extracted by3 mL of CH₂Cl₂. The organic layer was washed out with water two times.All water was removed after this and the product was forwarded for thefurther drying. Purification of the compounds was performed viapreparative HPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Amino/Amide Synthesis

1.6 mmol of Reagent A (in case of amine salt, an additional 1.5equivalent amount of DIPEA was added to the reaction mixture), 1.7 mmolof Reagent B, were added to 1 mL of a solution of 200 gBenzotriazole-N-oxide in 1 L of DMF. To the stirred mixture 1.9 mmol ofEDC was then added. The resulting mixture was stirred at roomtemperature for 72 hours. The mixture was then diluted with 5 ml of 1%sodium phosphate solution, treated with ultrasound. After that 2 mL ofHCl solution in 1,4-dioxane was added and the mixture was treated withultrasound for 4 hours. The solid or oily crude product formed wasisolated and purified via preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Oxypyrimidine Synthesis

A small vial was charged with 1.6 mmol of Reagent A, 1.6 mmol of ReagentBand 1 ml of 4M dioxane solution of HCl. The vial was heated at 100° C.for 4 h. In case reaction mixture was too viscous additional 0.5 ml ofdioxane were added. Then it was diluted with 3 ml of water and extractedby 3 mL of CHCl₃. Organic layer was washed with water (2*2 mL), driedand evaporated. The solid residue was purified by preparativechromatography. In case of reasonable amount of residue formed duringextraction procedure it was separated from solution and purified bypreparative chromatography. Purification of the compounds was performedvia preparative HPLC on Agilent 1260 Infinity systems equipped with DADand mass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Enamine Synthesis

A vial was charged with 1.6 mmol of Reagent A, 1 ml of DMF and 1.6 mmolof Reagent B. The reaction mixture was stirred and heated at 100° C. for4 h. Then it was cooled to rt. In case of residue formed it was filteredoff and purified by preparative chromatography. Otherwise the reactionmixture was diluted with 3 ml of water and extracted by 3 mL of CHCl₃.The organic layer was washed with water (2*2 mL), dried and evaporated.The solid residue was purified by preparative HPLC on Agilent 1260Infinity systems equipped with DAD and mass-detectors. Waters SunfireC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 PrepGuard Cartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Halogen Displacement: Carbon-Oxygen/Nitrogen/Sulfur Bond Formation

To a stirred solution containing 0.6 mmol of Reagent A (in case of aminesalt, an additional 1.5 equivalent amount of DIPEA was added to thereaction mixture), 0.72 mmol of DIPEA, 80 mg of potassium iodide in 1 mLof DMF and 0.6 mmol of Reagent B was added. The reaction mixture wasallowed to stir on a boiling water bath for ca. 5 min. Upon a completedissolution of the reagents the stirred reaction mixture was heated onthe water bath for the time specified on the vial label. The reactionmixture was triturated with an excess of deionized water and sonicateduntil a crystalline precipitate was formed. In case the trituration withwater did not cause the product precipitation 1 mL of 2-propanol withthe subsequent sonication were applied instead. The precipitate wasfiltered, washed twice with methanol, and dried. Purification of thecompounds was performed via preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

A vial was charged with 0.6 mmol of Reagent A (in case of amine salt, anadditional 1.5 equivalent amount of DIPEA was added to the reactionmixture), dry DMF (2 mL), and 1.4 mmol of DIPEA. To the stirred reactionmixture 0.6 mmol of Reagent B was added. The firmly closed reaction vialwas placed into a water bath and the reaction mixture was stirred at100° C. until a complete dissolution of the reaction component occurs.Then the homogeneous reaction mixture was heated in the water bath at100° C. for 6 hrs. The vial was passed to the polymer scavengerpurification. The solvent was removed under reduced pressure. Ethylacetate (10 mL) and then wet anion resin (5 g) were added to theresidue. The stirred mixture was heated in a water bath at 70° C. for 6hrs. Then the resin was filtered off. The solution was transferred intoa pre-weighted vial and the solvent was removed under reduced pressure.Purification of the compounds was performed via preparative HPLC onAgilent 1260 Infinity systems equipped with DAD and mass-detectors.Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm withSunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10 mm was used.Solvents used were deionized Water (phase A) and HPLC-grade Methanol(phase B). Preset chromatography gradient methods were chosen on thebasis of compound properties.

Amine Synthesis: Mannich Reaction

A vial was charged with 1.6 mmol of Reagent A, 2 ml of methanol and 6.4mmol of formaline. If the solution was not homogenous additional 0.5 mLof methanol were added. The reaction mixture was sonicated for 1 h. Then1.6 mmol of Reagent B were added and sonicated for another 1 h. In caseof substantial amount of residue formed it was filtered off, washed byiPrOH (water then iPrOH if TEA is present in the reaction mixture) andpurified by preparative HPLC. Otherwise the reaction mixture was dilutedwith 3 mL of water and extracted by 3 mL of CHCl₃. The organic layer waswashed with water (2*2 mL), dried and evaporated. The solid residue waspurified by preparative HPLC on Agilent 1260 Infinity systems equippedwith DAD and mass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å,5 μm, 19 mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm,19 mm×10 mm was used. Solvents used were deionized Water (phase A) andHPLC-grade Methanol (phase B). Preset chromatography gradient methodswere chosen on the basis of compound properties.

Oxamide Synthesis

A vial was charged with 1.6 mmol of Reagent A, 1 mL of acetonitrile, 2.9mmol of DIPEA and 1.6 mmol of ethyl chlorooxalate. The reaction mixturewas stirred for 30 min at rt and 1.76 mmol of Reagent B were added. Thevial was heated at 100° C. for 6 h. The reaction mixture was cooled tort, diluted with 3 mL of water and extracted by 3 mL of CHCl₃. Theorganic layer was washed with water (2*2 mL), dried and evaporated. Thesolid residue was purified by preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Ether Synthesis

A small vial was charged with 0.6 mmol of Reagent A (in case of aminesalt, an additional 1.5 equivalent amount of DIPEA was added to thereaction mixture), followed by 80 mg of potassium iodide in 0.7 mL DMF,and then 0.6 mmol of Reagent B. After stirring 1 mL 4M solution of KOHin methanol was added, the vial was closed tightly and shaked. Next thevial was sonicated for 24 h at the temperature no more than 35° C. Afterthat the vial was filled with chloroform to the brim. After stirring theorganic layer was washed twice with water and dried. Purification of thecompounds was performed via preparative HPLC on Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Bicyclic Synthesis

A vial was charged with 1.6 mmol of Reagent A, 1 mL of pyridine and 1.6mmol of Reagent B, stirred. Then 6.4 mmol of Me₃SiCl were added and thereaction mixture was stirred and heated at 100° C. for 8 h. Then it wascooled to rt and 1.9 mmol of TEA were added and the vial was heated foranother 30 min at 100° C. Then the reaction mixture was diluted with 3ml of water and extracted by 3 mL of CHCl₃. The organic layer was washedwith water (3*2 mL), dried and evaporated. The solid residue waspurified by preparative HPLC on Agilent 1260 Infinity systems equippedwith DAD and mass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å,5 μm, 19 mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm,19 mm×10 mm was used. Solvents used were deionized Water (phase A) andHPLC-grade Methanol (phase B). Preset chromatography gradient methodswere chosen on the basis of compound properties.

Methyl Amine Synthesis: Reductive Amination

0.6 mmol of Reagent A (in case of amine salt, an additional 1.5equivalent amount of DIPEA was added to the reaction mixture) wasdissolved in 3 mL of methanol and the reaction mixture was stirred in avial at r. t. Then 0.6 mmol of Reagent B was added to the stirredsolution. The vial with the reaction mixture was sonicated at 58-60° C.for 60-90 min until a complete dissolution of the reagents. Up to 5 mLof acetonitrile could be added to complete the dissolution of thereagents. The reaction vial was cooled to 0° C. and sodium borohydride(150 mg) was added to the reaction mixture in small portions. Thereaction mixture was stirred in the open vial until sodium borohydridewas dissolved. The reaction vial was sonicated for 2 hrs at r. t.,closed, and allowed to stand overnight at r. t. Then the open reactionvial was sonicated at 50° C. until methanol was nearly completelyevaporated. The reaction mixture was triturated with 5 mL of methanoland stirred until the large part of it was dissolved. The insoluble partlargely consisted of inorganic salts. The product was purified bypassing the methanolic suspension through ionic polymer scavengers. Inthe case of an incomplete dissolution of the product in methanol 5 mL ofdeionized water could be added to the methanolic suspension causingprecipitation of the product and dissolution of the inorganiccontaminants. In the case of an emulsion formation upon addition ofmethanol the reaction mixture was filtered through a smallchromatographic column filled with 8 g of silica gel. The product waseluted with methanol and the solvent removed under reduced pressure toyield the product. Purification of the compounds was performed viapreparative HPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Sulfonamide Synthesis

A vial was charged with 0.6 mmol of Reagent A (in case of amine salt, anadditional 1.5 equivalent amount of DIPEA was added to the reactionmixture), acetonitrile (1 mL), and 0.72 mmol of triethylamine. To thestirred reaction mixture 0.6 mmol of Reagent B was added. The vial wasplaced in a water bath and heated at 100° C. for 2 hrs. 2% Hydrochloricacid (2 mL) was added to the reaction mixture and the vial was shaken.In case a solid precipitate was formed the vial was passed to thefiltration. In case an oily product was formed the vial was sonicated tocause the crystallization. Additional measures to cause thecrystallization of the oily product, e.g., varying the amount of waterand an increase of the sonication time, can be taken. Purification ofthe compounds was performed via preparative HPLC on Agilent 1260Infinity systems equipped with DAD and mass-detectors. Waters SunfireC18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 PrepGuard Cartridge, 100 Å, 10 μm, 19 mm×10 mm was used. Solvents used weredeionized Water (phase A) and HPLC-grade Methanol (phase B). Presetchromatography gradient methods were chosen on the basis of compoundproperties.

Sulfide Synthesis

A vial was charged with 1.6 mmol of Reagent A, 0.7 ml of DMF and 1.76mmol of thiourea. The reaction mixture was stirred and heated at 100° C.for 2 h. Then it was cooled to rt and 1 mL of 4M KOH solution and 1.6mmol of Reagent B were added. The reaction mixture was sonicated for 24h. Then it was diluted with 3 mL of water and extracted by 3 mL ofCHCl₃. In case of residue formed it was filtered off and purified bypreparative chromatography. The organic layer was washed with water (2*2mL), dried and evaporated. The solid residue was purified by preparativeHPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Sulfone Synthesis

A vial was charged with 1.6 mmol of Reagent A, 1 mL of i-PrOH, 1.6 mmolof Reagent B and 1 mL of 4M KOH solution. The reaction mixture wassonicated at 50-60° C. for 2 h. Then 1 ml of methanol, 0.175 mL ofCH₃COOH, 0.45 mL of 50% H₂O₂ and 0.175 mL of 10% solution of ammoniummolibdate were added. The reaction mixture was sonicated at 70° C. for 5h. Then it was diluted with 3 mL of water and extracted by 3 mL ofCHCl₃. In case of residue formed it was filtered off and purified bypreparative chromatography. The organic layer was washed with 10% NaHCO₃solution (5 mL), dried and evaporated. The solid residue was purified bypreparative HPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C₁₈ OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Thiazole Synthesis

A vial was charged with 1.6 mmol of Reagent A, 1.5 mL of DMF and 1.6mmol of Reagent B. The reaction mixture was heated at 100° C. for 2hours. After cooling to rt 0.2 ml of DIPEA, 3 mL of water were added andextracted by 3 mL of CHCl₃. Organic layer was washed by water (2*1 mL),dried and evaporated. The solid residue was purified via preparativeHPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Urea Synthesis

A vial was charged with 0.6 mmol of Reagent A (in case of amine salt, anadditional 1.5 equivalent amount of DIPEA was added to the reactionmixture), 2 mL of acetonitrile and 0.6 mmol of DIPEA. The vial was leftfor 30 minutes, then 0.6 mmol of Reagent B was loaded. A vial was placedin a boiling water bath and heated up for 8 hours, then left for 30minutes to cool down. 1 mL of water was added to the mixture and thevial was sonicated. If the residue has crystallized, the mixture wasstirred until uniform and passed to filtration, otherwise the water wasadded until vial was full and standard workup was used. Filtered solidwas washed with 1 ml of 1:1 isopropyl alcohol-water mixture 2 times.Purification of the compounds was performed via preparative HPLC onAgilent 1260 Infinity systems equipped with DAD and mass-detectors.Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×100 mm withSunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10 mm was used.Solvents used were deionized Water (phase A) and HPLC-grade Methanol(phase B). Preset chromatography gradient methods were chosen on thebasis of compound properties.

A vial was charged with 0.6 mmol of Reagent A (in case of amine salt, anadditional 1.5 equivalent amount of DIPEA was added to the reactionmixture), 2 mL of acetonitrile, 0.9 mmol of DIPEA, and then 0.6 mmol of2,2,2-trifluoroethylcloroformate dropwise. After left for 0.5 hrs, 0.73mmol of Reagent B was added to the mixture. The vial was placed in thewater boiling bath for 8 hrs. After 0.5 hrs cooling down 1 mL of waterwas added and the vial was passed to sonication. The outcome precipitatewas filtered and washed twice with 1 ml of 50% water solution of2-propanol). Purification of the compounds was performed via preparativeHPLC on Agilent 1260 Infinity systems equipped with DAD andmass-detectors. Waters Sunfire C18 OBD Prep Column, 100 Å, 5 μm, 19mm×100 mm with SunFire C18 Prep Guard Cartridge, 100 Å, 10 μm, 19 mm×10mm was used. Solvents used were deionized Water (phase A) and HPLC-gradeMethanol (phase B). Preset chromatography gradient methods were chosenon the basis of compound properties.

Piperidino-Oxypyrimidine Synthesis

Step A: To a solution of compound 1 (50.0 g, 290 mmol) in chloroform(400 mL) Me₃OBF₄ (34.5 g, 220 mmol) was added. The resulting mixture wasstirred at room temperature for 6 h and then washed with saturatedaqueous solution of K₂CO₃ (2×300 mL). The organic layer was separated,dried over MgSO₄, and evaporated in vacuo. The residue was purified byvacuum distillation (b.p. 78° C. at 1 torr) to give 45.6 g (247 mmol,85%) of compound 2 as a colorless oil.

Step B: Na (12.7 g, 550 mmol) was dissolved in EtOH (200 mL). Compound 3(37.5 g, 238 mmol) was added to the solution and the resulting mixturewas stirred at room temperature for 0.5 h. Then compound 2 (45.6 g, 247mmol) was added, the reaction was refluxed for 4 h, and then evaporatedunder reduced pressure. The residue was dissolved in water andneutralized with 10% HCl. The precipitated solid was filtered andre-crystallized from i-PrOH to yield 40.8 g (179 mmol, 75%) of compound4 as white solid.

Step C: To a suspension of compound 4 (0.020 g, 0.088 mmol) of in dryacetonitrile (2 mL) a solution of 10% HCl in dry dioxane was addeddropwise until pH 3. After standing for 0.5 h the solvents were removedin vacuum to obtain 0.023 g (0.088 mmol, 100%) of target compound 5.

Step D: To a solution of compound 4 (0.150 g, 0.66 mmol) and DIPEA(0.256 g, 1.98 mmol) in acetonitrile the corresponding acid chloride wasadded (1-3 eq.). The resulting mixture was stirred under reflux for 3hours and then evaporated in vacuo. The residue was purified by HPLC.The obtained product was suspended in dry acetonitrile. 10% HCl in drydioxane was added dropwise until pH 3. After standing for 0.5 h thesolvents were removed under reduced pressure to yield target amides 6.

Step E: To a solution of compound 4 (0.150 g, 0.66 mmol) in acetonitrile[(4-methoxybenzyl)oxy]acetic acid (0.129 g, 0.66 mmol), DIPEA (0.46 mL,2.64 mmol), and DMAP (0.005 g, 0.04 mmol) were added. Then TBTU (0.847g, 2.64 mmol) was added, the resulting mixture was refluxed for 8 hours,and evaporated under reduced pressure. The residue was purified by HPLCto yield the target amide 6.

Step A: To a solution of compound 1 (50.0 g, 290 mmol) in chloroform(400 mL) Me₃OBF₄ (34.5 g, 220 mmol) was added. The resulting mixture wasstirred at room temperature for 6 h and then washed with saturatedaqueous solution of K₂CO₃ (2×300 mL). The organic layer was separated,dried over MgSO₄, and evaporated in vacuo. The residue was purified byvacuum distillation (b.p. 78° C. at 1 torr) to give 45.6 g (247 mmol,85%) of compound 2 as a colorless oil.

Step B: Na (12.7 g, 550 mmol) was dissolved in EtOH (200 mL). Compound 3(37.5 g, 238 mmol) was added to the solution and the resulting mixturewas stirred at room temperature for 0.5 h. Then compound 2 (45.6 g, 247mmol) was added, the reaction was refluxed for 4 h, and then evaporatedunder reduced pressure. The residue was dissolved in water andneutralized with 10% HCl. The precipitated solid was filtered andre-crystallized from i-PrOH to yield 40.8 g (179 mmol, 75%) of compound4 as white solid.

Step C: To a solution of compound 4 (0.150 g, 0.66 mmol) and DIPEA(0.256 g, 1.98 mmol) in acetonitrile corresponding sulfonyl chloride(0.99 mmol, 1.5 equiv.) was added. The resulting mixture was stirredunder reflux for 2 h and then evaporated in vacuo. The residue waspurified by HPLC to yield the target compounds 5.

Step D: To a solution of compound 4 (0.150 g, 0.66 mmol) and DIPEA(0.256 g, 1.98 mmol) in acetonitrile the corresponding acid chloride wasadded (1.3-4 eq.). The resulting mixture was stirred under reflux for 3h and then evaporated in vacuo. The residue was purified by HPLC toyield the target amides 6.

Thieno-Oxypyrimidine Synthesis

Step A: To a solution compound 1 (30 g, 0.19 mol) in 300 mL dioxane HClwas added compound 2 (23.85 g, 0.23 mol). The reaction mixture wasstirred at rt overnight, diluted dioxane (300 mL), refluxed for 3 h,cooled and evaporated. The resulting residue was washed by mixtureEtOAc-iPrOH (1:2). The yield was 36 g (0.157 mol, 83%).

Step B: To a solution compound 3 (36 g, 0.157 mol) in 650 mL acetic acidbromine (35 mL) was added at rt. The reaction mixture was refluxed 48 h,cooled, evaporated, diluted with water. The resulting precipitate wasfiltered, washed with water and dried. The yield was 45 g (0.146 mol,93%).

Step C: The mixture compound 4 (35 g, 0.114 mol) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane CAS95464054 (2% mol) in methanol (500 ml) was stirredovernight under CO (10 bar) in autoclave. The reaction mixture wasfiltered and evaporated. The resulting residue was washed with water anddried. The yield was 26 g (0.091 mol, 80%).

Step D: Compound 5 (16 g, 0.055 mol) was added to a solution NaOH (21 g,0.525 mol) in 600 mL methanol. The reaction mixture was refluxedovernight, evaporated. The solid residue was washed by water andair-dried. The yield was 12.7 g (0.046 mol, 84%).

Step A: The mixture of compound 1 (50 g, 0.318 mol), compound 2 (54.86g, 0.477 mol) and methylsulfonylmethane (150.6 g, 1.59 mol) was refluxedovernight, cooled and evaporated. The resulting residue was washedmixture EtOAc-iPrOH (1:2). The yield was 41.65 g (0.249 mol, 78%).

Step B: To a solution compound 3 (41.65 g, 0.249 mol) in 700 mL aceticacid was added bromine (42 mL) at rt. The reaction mixture was refluxed48 h, cooled, evaporated, diluted with water. The resulting precipitatewas filtered, washed with water and dried. The yield was 51 g (0.207mol, 83%).

Step C: The mixture of compound 4 (35 g, 0.142 mol) and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane CAS95464054 (2% mol) in methanol (500 ml) was stirredovernight under CO (10 bar) in autoclave. The reaction mixture wasfiltered and evaporated. The resulting residue was washed with water anddried. The yield was 28 g (0.124 mol, 88%).

Step D: Compound 5 (15 g, 0.067 mol) was added to a solution of NaOH (20g, 0.5 mol) in 600 mL methanol. The reaction mixture was refluxedovernight, evaporated. The solid residue was washed by water andair-dried. The yield was 11.2 g (0.053 mol, 79%).

Amide synthesis from compound 6: The mixture of 1.1 eq of acid 6 and 1eq of corresponding amine was dissolved in 1 ml of HOBt solution in DMF(9.5% wt). Then 1.2 eq of EDC was added and reaction mixture was leftstirring at rt overnight (16-18 h). After completion of the reaction,monitored by LCMS, the reaction mixture was diluted with 4 mL ofdistilled water and left at ultrasonic bath for 30-40 min. The resultingresidue was filtered off, washed by water and dried under high vacuum.If there was no residue formed the aqueous solution was extracted by 4mL of DCM and the organic layer was washed by water (2*4 mL) and thesolvent was removed under reduced pressure. In case of low purity of thefinal compound was subjected to preparative HPLC purification.

Purification and Analytical Procedures:

Purification was performed using HPLC (H₂O-MeOH; Agilent 1260 Infinitysystems equipped with DAD and mass-detectors. Waters Sunfire C18 OBDPrep Column, 100 Å, 5 μm, 19 mm×100 mm with SunFire C18 Prep GuardCartridge, 100 Å, 10 μm, 19 mm×10 mm) The material was dissolved in 0.7mL DMSO. Flow: 30 mL/min. Purity of the obtained fractions was checkedvia the analytical LCMS. Spectra were recorded for each fraction as itwas obtained straight after chromatography in the solution form. Thesolvent was evaporated under the N2 flow upon heating to 80° C. On thebasis of post-chromatography LCMS analysis fractions were united. Solidfractions were dissolved in 0.5 mL MeOH and transferred into apre-weighted marked vials. Obtained solutions were again evaporatedunder the N2 flow upon heating to 80° C. After drying, products werefinally characterized by LCMS and ¹H NMR.

NMR Instrument specifications: Bruker AVANCE DRX 500, Varian UNITYplus400.

LC/MS Instrument specifications: Agilent 1100 Series LC/MSD system withDAD\ELSD and Agilent LC\MSD VL (G1956A), SL (G1956B) mass-spectrometer.Agilent 1200 Series LC/MSD system with DAD\LSD and Agilent LC\MSD SL(G6130A), SL (G6140A) mass-spectrometer. All the LC/MS data wereobtained using positive/negative mode switching. Column Zorbax SB-C181.8 μm 4.6×15 mm Rapid Resolution cartridge (PN 821975-932) Mobile phaseA—acetonitrile, 0.1% formic acid, B—water (0.1% formic acid) Flow rate 3ml/min Gradient 0 min—100% B, 0.01 min—100% B, 1.5 min—0% B, 1.8 min—0%B, 1.81 min—100% B. Injection volume 1 μl. Ionization mode atmosphericpressure chemical ionization (APCI). Scan range m/z 80-1000

TABLE 1 Mass Spectral Data M + H M + H Compound MW (calculated)(observed)

265 229.1 229.2

399 363.1 363.0

406 407.2 407.2

427 391.2 391.2

420 384.2 384.0

411 375.2 375.1

435 399.2 399.2

328 329.2 329.2

323 324.1 324.2

376 377.1 377.2

396 397.1 397.2

368 369.1 369.2

376 377.2 377.2

437 437.2 437.1

332 333.1 333.2

333 334.1 334.0

375 376.2 376.2

246 245.9 246.0

292 293.1 293.0

322 323.1 323.0

350 351.1 351.0

350 351.2 351.2

363 364.1 364.2

361 362.1 362.2

355 356.1 356.1

356 357.1 357

308 309.1 309.0

344 308.1 308.2

365 366.1 366.0

326 327.1 327.0

342 343.1 343.2

329 330.1 330.2

315 316.1 316.0

340 341.1 341.2

400 401.1 401.0

308 307.9 308.0

354 355.1 355.2

384 385.1 385.0

413 413.2 413.2

413 413.2 413.2

426 426.2 426.0

423 424.2 424.2

417 418.1 418.2

418 419.1 419.0

417 418.1 418.2

370 371.1 371.0

442 370.1 370.2

427 428.1 428.0

388 389.1 389.2

404 405.1 405.0

391 392.1 392.2

377 378.1 378.2

402 403.1 403.0

463 463.2 463.2

243 244.3 244.0

278 278.0 278.0

305 306.1 306.0

340 340.0 339.9

289 290.1 290.2

290 291.1 291.0

351 352.1 352.2

315 316.1 316.0

377 377.0 377.0

298 299.1 299.1

308 307.9 308.0

229 230.0 230.0

312 313.1 313.0

356 356.2 356.2

6. PHARMACEUTICAL COMPOSITIONS

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of compounds provided herein and apharmaceutically acceptable carrier, diluent or excipient.

The compounds can be formulated into suitable pharmaceuticalpreparations such as solutions, suspensions, tablets, dispersibletablets, pills, capsules, powders, sustained release formulations orelixirs, for oral administration or in sterile solutions or suspensionsfor ophthalmic or parenteral administration, as well as transdermalpatch preparation and dry powder inhalers. Typically the compoundsdescribed above are formulated into pharmaceutical compositions usingtechniques and procedures well known in the art (see, e.g., AnselIntroduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable salts is (are) mixed with a suitablepharmaceutical carrier or vehicle. In certain embodiments, theconcentrations of the compounds in the compositions are effective fordelivery of an amount, upon administration, that treats, prevents, orameliorates one or more of the symptoms and/or progression of a diseaseor disorder disclosed herein.

Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. For example,liposome formulations may be prepared as known in the art. Briefly,liposomes such as multilamellar vesicles (MLV's) may be formed by dryingdown egg phosphatidyl choline and brain phosphatidyl serine (7:3 molarratio) on the inside of a flask. A solution of a compound providedherein in phosphate buffered saline lacking divalent cations (PBS) isadded and the flask shaken until the lipid film is dispersed. Theresulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in in vitro and in vivo systems described hereinand then extrapolated therefrom for dosages for humans. In someembodiments, the active compound is administered in a method to achievea therapeutically effective concentration of the drug. In someembodiments, a companion diagnostic (see, e.g., Olsen D and Jorgensen JT, Front. Oncol., 2014 May 16, 4:105, doi: 10.3389/fonc.2014.00105) isused to determine the therapeutic concentration and safety profile ofthe active compound in specific patients or patient populations.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, tissue distribution, inactivation andexcretion rates of the active compound, the physicochemicalcharacteristics of the compound, the dosage schedule, and amountadministered as well as other factors known to those of skill in theart. For example, the amount that is delivered is sufficient toameliorate one or more of the symptoms of a disease or disorderdisclosed herein.

In certain embodiments, a therapeutically effective dosage shouldproduce a serum concentration of active ingredient of from about 0.1ng/mL to about 50-100 μg/mL. In one embodiment, the pharmaceuticalcompositions provide a dosage of from about 0.001 mg to about 2000 mg ofcompound per kilogram of body weight per day. Pharmaceutical dosage unitforms are prepared to provide from about 1 mg to about 1000 mg and incertain embodiments, from about 10 to about 500 mg of the essentialactive ingredient or a combination of essential ingredients per dosageunit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable salts thereofare mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating, retardingprogression, or preventing. The concentration of active compound in thecomposition will depend on absorption, tissue distribution,inactivation, excretion rates of the active compound, the dosageschedule, amount administered, particular formulation as well as otherfactors known to those of skill in the art.

The compositions are intended to be administered by a suitable route,including but not limited to oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, intrathecal, mucosal,dermal, transdermal, buccal, rectal, topical, local, nasal orinhalation. For oral administration, capsules and tablets can beformulated. The compositions are in liquid, semi-liquid or solid formand are formulated in a manner suitable for each route ofadministration.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol, dimethylacetamide or other synthetic solvent; antimicrobial agents, such asbenzyl alcohol and methyl parabens; antioxidants, such as ascorbic acidand sodium bisulfite; chelating agents, such asethylenediaminetetraacetic acid (EDTA); buffers, such as acetates,citrates and phosphates; and agents for the adjustment of tonicity suchas sodium chloride or dextrose. Parenteral preparations can be enclosedin ampules, pens, disposable syringes or single or multiple dose vialsmade of glass, plastic or other suitable material.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease, disorder or condition treatedand may be empirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablesalts thereof. The pharmaceutically therapeutically active compounds andsalts thereof are formulated and administered in unit dosage forms ormultiple dosage forms. Unit dose forms as used herein refer tophysically discrete units suitable for human and animal subjects andpackaged individually as is known in the art. Each unit dose contains apredetermined quantity of the therapeutically active compound sufficientto produce the desired therapeutic effect, in association with therequired pharmaceutical carrier, vehicle or diluent. Examples of unitdose forms include ampules and syringes and individually packagedtablets or capsules. Unit dose forms may be administered in fractions ormultiples thereof. A multiple dose form is a plurality of identical unitdosage forms packaged in a single container to be administered insegregated unit dose form. Examples of multiple dose forms includevials, bottles of tablets or capsules or bottles of pints or gallons.Hence, multiple dose form is a multiple of unit doses which are notsegregated in packaging.

Sustained-release preparations can also be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the compound provided herein,which matrices are in the form of shaped articles, e.g., films, ormicrocapsule. Examples of sustained-release matrices includeiontophoresis patches, polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides,copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradableethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymerssuch as the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate), andpoly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinylacetate and lactic acid-glycolic acid enable release of molecules forover 100 days, certain hydrogels release proteins for shorter timeperiods. When encapsulated compound remain in the body for a long time,they may denature or aggregate as a result of exposure to moisture at37° C., resulting in a loss of biological activity and possible changesin their structure. Rational strategies can be devised for stabilizationdepending on the mechanism of action involved. For example, if theaggregation mechanism is discovered to be intermolecular S—S bondformation through thio-disulfide interchange, stabilization may beachieved by modifying sulfhydryl residues, lyophilizing from acidicsolutions, controlling moisture content, using appropriate additives,and developing specific polymer matrix compositions.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non toxic carrier may beprepared. For oral administration, a pharmaceutically acceptable nontoxic composition is formed by the incorporation of any of the normallyemployed excipients, such as, for example pharmaceutical grades ofmannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions may contain about 0.001% 100% activeingredient, in certain embodiments, about 0.185% or about 75-95%.

The active compounds or pharmaceutically acceptable salts may beprepared with carriers that protect the compound against rapidelimination from the body, such as time release formulations orcoatings.

The compositions may include other active compounds to obtain desiredcombinations of properties. The compounds provided herein, orpharmaceutically acceptable salts thereof as described herein, may alsobe advantageously administered for therapeutic or prophylactic purposestogether with another pharmacological agent known in the general art tobe of value in treating one or more of the diseases or medicalconditions referred to hereinabove, such as diseases related tooxidative stress. It is to be understood that such combination therapyconstitutes a further aspect of the compositions and methods oftreatment provided herein.

Lactose-free compositions provided herein can contain excipients thatare well known in the art and are listed, for example, in the U.S.Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-freecompositions contain an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Exemplary lactose-free dosage forms contain an activeingredient, microcrystalline cellulose, pre-gelatinized starch andmagnesium stearate.

Further encompassed are anhydrous pharmaceutical compositions and dosageforms containing a compound provided herein. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms provided hereincan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are anhydrous ifsubstantial contact with moisture and/or humidity during manufacturing,packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are packaged using materials known to prevent exposure towater such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs and strip packs.

Oral Dosage Forms

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich may be enteric coated, sugar coated or film coated. Capsules maybe hard or soft gelatin capsules, while granules and powders may beprovided in non effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms, such ascapsules or tablets. The tablets, pills, capsules, troches and the likecan contain any of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof, and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable salt thereof asdescribed herein. Higher concentrations, up to about 98% by weight ofthe active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric coated tablets, because of theenteric coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents may also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted from noneffervescent granules and effervescent preparations reconstituted fromeffervescent granules. Aqueous solutions include, for example, elixirsand syrups. Emulsions are either oil in-water or water in oil. In someembodiments, the suspension is a suspension of microparticles ornanoparticles. In some embodiments, the emulsion is an emulsion ofmicroparticles or nanoparticles.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used in noneffervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic adds include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is encapsulated ina gelatin capsule. Such solutions, and the preparation and encapsulationthereof, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. For a liquid dosage form, the solution, e.g., for example, ina polyethylene glycol, may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be easilymeasured for administration.

Alternatively, liquid or semi solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include, but are not limited to, those containing acompound provided herein, a dialkylated mono- or poly-alkylene glycol,including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme,tetraglyme, polyethylene glycol-350-dimethyl ether, polyethyleneglycol-550-dimethyl ether, polyethylene glycol-750-dimethyl etherwherein 350, 550 and 750 refer to the approximate average molecularweight of the polyethylene glycol, and one or more antioxidants, such asbutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl) acetals of lower alkyl aldehydes such asacetaldehyde diethyl acetal.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

Injectables, Solutions and Emulsions

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. In someembodiments, the suspension is a suspension of microparticles ornanoparticles. In some embodiments, the emulsion is an emulsion ofmicroparticles or nanoparticles. Suitable excipients are, for example,water, saline, dextrose, glycerol or ethanol. In addition, if desired,the pharmaceutical compositions to be administered may also containminor amounts of non toxic auxiliary substances such as wetting oremulsifying agents, pH buffering agents, stabilizers, solubilityenhancers, and other such agents, such as for example, sodium acetate,sorbitan monolaurate, triethanolamine oleate and cyclodextrins.Implantation of a slow release or sustained release system, such that aconstant level of dosage is maintained is also contemplated herein.Briefly, a compound provided herein is dispersed in a solid innermatrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticizedor unplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propyl phydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit dose parenteral preparations are packaged in an ampule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,such as more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

Lyophilized Powders

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable salt thereof, in asuitable solvent. The solvent may contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose or other suitable agent. Thesolvent may also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at, inone embodiment, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. Generally,the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage (including butnot limited to 10-1000 mg or 100-500 mg) or multiple dosages of thecompound. The lyophilized powder can be stored under appropriateconditions, such as at about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1-50 mg, about 5-35 mg, or about 9-30 mg oflyophilized powder, is added per mL of sterile water or other suitablecarrier. The precise amount depends upon the selected compound. Suchamount can be empirically determined.

Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsion or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable salts thereof may beformulated as aerosols for topical application, such as by inhalation(see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma). These formulations foradministration to the respiratory tract can be in the form of an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the formulation will have diameters of less than50 microns or less than 10 microns.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono, di andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. An exemplary weight of a rectalsuppository is about 2 to 3 grams.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

Sustained Release Compositions

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and U.S. Pat. Nos. 4,008,719, 5,674,533, 5,059,595,5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480,5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945,5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363,6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358,6,699,500 and 6,740,634, each of which is incorporated herein byreference. Such dosage forms can be used to provide slow orcontrolled-release of one or more active ingredients using, for example,hydropropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled-releaseformulations known to those of ordinary skill in the art, includingthose described herein, can be readily selected for use with the activeingredients provided herein.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. In one embodiment, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. In certain embodiments,advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the agent may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In one embodiment, a pump may be used(see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald etal., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574(1989). In another embodiment, polymeric materials can be used. In yetanother embodiment, a controlled release system can be placed inproximity of the therapeutic target, i.e., thus requiring only afraction of the systemic dose (see, e.g., Goodson, Medical Applicationsof Controlled Release, vol. 2, pp. 115-138 (1984).

In some embodiments, a controlled release device is introduced into asubject in proximity of the site of inappropriate immune activation or atumor. Other controlled release systems are discussed in the review byLanger (Science 249:1527-1533 (1990). The active ingredient can bedispersed in a solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient contained in such parenteral compositions is highlydependent on the specific nature thereof, as well as the needs of thesubject.

Targeted Formulations

The compounds provided herein, or pharmaceutically acceptable saltsthereof, may also be formulated to be targeted to a particular tissue,receptor, or other area of the body of the subject to be treated,including liposome-, resealed erythrocyte-, and antibody-based deliverysystems. Many such targeting methods are well known to those of skill inthe art. All such targeting methods are contemplated herein for use inthe instant compositions. For non-limiting examples of targetingmethods, see, e.g., U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359,6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082,6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252,5,840,674, 5,759,542 and 5,709,874.

In one embodiment, the antibody-based delivery system is anantibody-drug conjugate (“ADC”), e.g., as described in Hamilton G S,Biologicals, 2015 September, 43(5):318-32; Kim E G and Kim K M, Biomol.Ther. (Seoul), 2015 November, 23(6):493-509; and Peters C and Brown S,Biosci. Rep., 2015 Jun. 12, 35(4) pii: e00225, each of which isincorporated herein by reference.

In one embodiment, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, may also be suitable aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art. For example, liposomeformulations may be prepared as described in U.S. Pat. No. 4,522,811.Briefly, liposomes such as multilamellar vesicles (MLV's) may be formedby drying down egg phosphatidyl choline and brain phosphatidyl serine(7:3 molar ratio) on the inside of a flask. A solution of a compoundprovided herein in phosphate buffered saline lacking divalent cations(PBS) is added and the flask shaken until the lipid film is dispersed.The resulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

Articles of Manufacture

The compounds or pharmaceutically acceptable salts can be packaged asarticles of manufacture containing packaging material, a compound orpharmaceutically acceptable salt thereof provided herein, which is usedfor treatment, prevention or amelioration of one or more symptoms orprogression of a disease or disorder disclosed herein, and a label thatindicates that the compound or pharmaceutically acceptable salt thereofis used for treatment, prevention or amelioration of one or moresymptoms or progression of a disease or disorder disclosed herein.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, pens,bottles, and any packaging material suitable for a selected formulationand intended mode of administration and treatment. A wide array offormulations of the compounds and compositions provided herein arecontemplated.

In certain embodiments, provided herein also are kits which, when usedby the medical practitioner, can simplify the administration ofappropriate amounts of active ingredients to a subject. In certainembodiments, the kit provided herein includes a container and a dosageform of a compound provided herein, including a single enantiomer or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, including a single enantiomer or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, in a container comprising one or more othertherapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

7. METHODS OF TREATMENT

7.1 Cancer

In one embodiment, provided herein is a method of treating or preventingcancer, which comprises administering to a patient a compound providedherein, or a derivative thereof.

In another embodiment, provided herein is method of managing cancer,which comprises administering to a patient a compound provided herein,or a derivative thereof.

Also provided herein are methods of treating patients who have beenpreviously treated for cancer but are non-responsive to standardtherapies, as well as those who have not previously been treated. Alsoprovided are methods of treating patients regardless of patient's age,although some diseases or disorders are more common in certain agegroups. Also provided are methods of treating patients who haveundergone surgery in an attempt to treat the disease or condition atissue, as well as those who have not. Because patients with cancer haveheterogeneous clinical manifestations and varying clinical outcomes, thetreatment given to a patient may vary, depending on his/her prognosis.The skilled clinician will be able to readily determine without undueexperimentation specific secondary agents, types of surgery, and typesof non-drug based standard therapy that can be effectively used to treatan individual patient with cancer.

As used herein, the term “cancer” includes, but is not limited to, solidtumors and blood borne tumors. The term “cancer” refers to disease ofskin tissues, organs, blood, and vessels, including, but not limited to,cancers of the bladder, bone, blood, brain, breast, cervix, chest,colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes,lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis,throat, and uterus. Specific cancers include, but are not limited to,advanced malignancy, amyloidosis, neuroblastoma, meningioma,hemangiopericytoma, multiple brain metastase, glioblastoma multiforms,glioblastoma, brain stem glioma, poor prognosis malignant brain tumor,malignant glioma, recurrent malignant giolma, anaplastic astrocytoma,anaplastic oligodendroglioma, neuroendocrine tumor, rectaladenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectalcarcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma,karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuselarge B-Cell lymphoma, low grade follicular lymphoma, malignantmelanoma, malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma

In certain embodiments, the cancer is a solid tumor. In certainembodiments, the solid tumor is metastatic. In certain embodiments, thesolid tumor is drug-resistant. In certain embodiments, the solid tumoris hepatocellular carcinoma, prostate cancer, pancreatic cancer, ovariancancer, or glioblastoma.

In certain embodiments, the cancer is a blood borne tumor. In certainembodiments, the blood borne tumor is metastatic. In certainembodiments, the blood borne tumor is drug resistant. In certainembodiments, the cancer is leukemia.

In one embodiment, methods provided herein encompass treating,preventing or managing various types of leukemias such as chroniclymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acutemyeloblastic leukemia (AML) by administering a therapeutically effectiveamount of a compound provided herein or a derivative thereof.

In some embodiments, the methods provided herein encompass treating,preventing or managing acute leukemia in a subject. In some embodiments,the acute leukemia is acute myeloid leukemia (AML), which includes, butis not limited to, undifferentiated AML (M0), myeloblastic leukemia(M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3variant [M3V]), myelomonocytic leukemia (M4 or M4 variant witheosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), andmegakaryoblastic leukemia (M7). In one embodiment, the acute myeloidleukemia is undifferentiated AML (M0). In one embodiment, the acutemyeloid leukemia is myeloblastic leukemia (M1). In one embodiment, theacute myeloid leukemia is myeloblastic leukemia (M2). In one embodiment,the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant[M3V]). In one embodiment, the acute myeloid leukemia is myelomonocyticleukemia (M4 or M4 variant with eosinophilia [M4E]). In one embodiment,the acute myeloid leukemia is monocytic leukemia (M5). In oneembodiment, the acute myeloid leukemia is erythroleukemia (M6). In oneembodiment, the acute myeloid leukemia is megakaryoblastic leukemia(M7). Thus, the methods of treating, preventing or managing acutemyeloid leukemia in a subject comprise the step of administering to thesubject an amount of a compound provided herein or a derivative thereofeffective to treat, prevent or manage acute myeloid leukemia alone or incombination. In some embodiments, the methods comprise the step ofadministering to the subject a compound provided herein or a derivativethereof in combination with a second active agent in amounts effectiveto treat, prevent or manage acute myeloid leukemia.

In some embodiments, the methods provided herein encompass treating,preventing or managing acute lymphocytic leukemia (ALL) in a subject. Insome embodiments, acute lymphocytic leukemia includes leukemia thatoriginates in the blast cells of the bone marrow (B-cells), thymus(T-cells), and lymph nodes. The acute lymphocytic leukemia can becategorized according to the French-American-British (FAB) MorphologicalClassification Scheme as L1—Mature-appearing lymphoblasts (T cells orpre-B-cells), L2—Immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells), and L3—Lymphoblasts (B-cells;Burkitt's cells). In one embodiment, the acute lymphocytic leukemiaoriginates in the blast cells of the bone marrow (B-cells). In oneembodiment, the acute lymphocytic leukemia originates in the thymus(T-cells). In one embodiment, the acute lymphocytic leukemia originatesin the lymph nodes. In one embodiment, the acute lymphocytic leukemia isL1 type characterized by mature-appearing lymphoblasts (T-cells orpre-B-cells). In one embodiment, the acute lymphocytic leukemia is L2type characterized by immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells). In one embodiment, the acutelymphocytic leukemia is L3 type characterized by lymphoblasts (B-cells;Burkitt's cells). In certain embodiments, the acute lymphocytic leukemiais T cell leukemia. In one embodiment, the T-cell leukemia is peripheralT-cell leukemia. In another embodiment, the T-cell leukemia is T-celllymphoblastic leukemia. In another embodiment, the T-cell leukemia iscutaneous T-cell leukemia. In another embodiment, the T-cell leukemia isadult T-cell leukemia. Thus, the methods of treating, preventing ormanaging acute lymphocytic leukemia in a subject comprise the step ofadministering to the subject an amount of a compound provided herein ora derivative thereof effective to treat, prevent or manage acutelymphocytic leukemia alone or in combination with a second active agent.In some embodiments, the methods comprise the step of administering tothe subject a compound provided herein or a derivative thereof incombination with a second active agent in amounts effective to treat,prevent or manage acute lymphocytic leukemia.

In some embodiments, the methods provided herein encompass treating,preventing or managing chronic myelogenous leukemia (CML) in a subject.The methods comprise the step of administering to the subject an amountof a compound provided herein or a derivative thereof effective totreat, prevent or manage chronic myelogenous leukemia. In someembodiments, the methods comprise the step of administering to thesubject a compound provided herein or a derivative thereof incombination with a second active agent in amounts effective to treat,prevent or manage chronic myelogenous leukemia.

In some embodiments, the methods provided herein encompass treating,preventing or managing chronic lymphocytic leukemia (CLL) in a subject.The methods comprise the step of administering to the subject an amountof a compound provided herein or a derivative thereof effective totreat, prevent or manage chronic lymphocytic leukemia. In someembodiments, the methods comprise the step of administering to thesubject a compound provided herein or a derivative thereof incombination with a second active agent in amounts effective to treat,prevent or manage chronic lymphocytic leukemia.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing disease in patients with impaired renalfunction. In certain embodiments, provided herein are method oftreating, preventing, and/or managing cancer in patients with impairedrenal function. In certain embodiments, provided herein are methods ofproviding appropriate dose adjustments for patients with impaired renalfunction due to, but not limited to, disease, aging, or other patientfactors.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing lymphoma, including non-Hodgkin's lymphoma.In some embodiments, provided herein are methods for the treatment ormanagement of non-Hodgkin's lymphoma (NHL), including but not limitedto, diffuse large B-cell lymphoma (DLBCL), using prognostic factors.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing multiple myeloma, includingrelapsed/refractory multiple myeloma in patients with impaired renalfunction or a symptom thereof, comprising administering atherapeutically effective amount of a compound provided herein, or aderivative thereof to a patient having relapsed/refractory multiplemyeloma with impaired renal function.

In certain embodiments, a therapeutically or prophylactically effectiveamount of the compound is from about 0.005 to about 1,000 mg per day,from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mgper day, from about 0.01 to about 100 mg per day, from about 0.1 toabout 100 mg per day, from about 0.5 to about 100 mg per day, from about1 to about 100 mg per day, from about 0.01 to about 50 mg per day, fromabout 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day,from about 1 to about 50 mg per day, from about 0.02 to about 25 mg perday, from about 0.05 to about 10 mg per day, from about 0.05 to about 5mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 toabout 5 mg per day.

In certain embodiments, the therapeutically or prophylacticallyeffective amount is about 0.1, about 0.2, about 0.5, about 1, about 2,about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10,about 15, about 20, about 25, about 30, about 40, about 45, about 50,about 60, about 70, about 80, about 90, about 100, or about 150 mg perday.

In one embodiment, the recommended daily dose range of the compoundprovided herein, or a derivative thereof, for the conditions describedherein lie within the range of from about 0.5 mg to about 50 mg per day,in one embodiment given as a single once-a-day dose, or in divided dosesthroughout a day. In some embodiments, the dosage ranges from about 1 mgto about 50 mg per day. In other embodiments, the dosage ranges fromabout 0.5 to about 5 mg per day. Specific doses per day include 0.1,0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.

In a specific embodiment, the recommended starting dosage may be 0.5, 1,2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, therecommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. Thedose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In aspecific embodiment, the compound can be administered in an amount ofabout 25 mg/day. In a particular embodiment, the compound can beadministered in an amount of about 10 mg/day. In a particularembodiment, the compound can be administered in an amount of about 5mg/day. In a particular embodiment, the compound can be administered inan amount of about 4 mg/day. In a particular embodiment, the compoundcan be administered in an amount of about 3 mg/day.

In certain embodiments, the therapeutically or prophylacticallyeffective amount is from about 0.001 to about 100 mg/kg/day, from about0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, fromabout 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day,0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, fromabout 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day,from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3mg/kg/day, from about 0.01 to about 2 mg/kg/day, from about 0.01 toabout 1 mg/kg/day, or from about 0.01 to about 0.05 mg/kg/day.

The administered dose can also be expressed in units other thanmg/kg/day. For example, doses for parenteral administration can beexpressed as mg/m²/day. One of ordinary skill in the art would readilyknow how to convert doses from mg/kg/day to mg/m²/day to given eitherthe height or weight of a subject or both (see,www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1mg/kg/day for a 65 kg human is approximately equal to 38 mg/m²/day.

In certain embodiments, the amount of the compound administered issufficient to provide a plasma concentration of the compound at steadystate, ranging from about 0.001 to about 500 μM, about 0.002 to about200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, fromabout 1 to about 50 μM, about 0.02 to about 25 μM, from about 0.05 toabout 20 μM, from about 0.1 to about 20 μM, from about 0.5 to about 20μM, or from about 1 to about 20 μM.

In other embodiments, the amount of the compound administered issufficient to provide a plasma concentration of the compound at steadystate, ranging from about 5 to about 100 nM, about 5 to about 50 nM,about 10 to about 100 nM, about 10 to about 50 nM or from about 50 toabout 100 nM.

As used herein, the term “plasma concentration at steady state” is theconcentration reached after a period of administration of a compoundprovided herein, or a derivative thereof. Once steady state is reached,there are minor peaks and troughs on the time dependent curve of theplasma concentration of the compound.

In certain embodiments, the amount of the compound administered issufficient to provide a maximum plasma concentration (peakconcentration) of the compound, ranging from about 0.001 to about 500μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01to about 50 μM, from about 1 to about 50 μM, about 0.02 to about 25 μM,from about 0.05 to about 20 μM, from about 0.1 to about 2 μM, from about0.5 to about 20 μM, or from about 1 to about 20 μM.

In certain embodiments, the amount of the compound administered issufficient to provide a minimum plasma concentration (troughconcentration) of the compound, ranging from about 0.001 to about 500μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01to about 50 μM, from about 1 to about 50 μM, about 0.01 to about 25 μM,from about 0.01 to about 20 μM, from about 0.02 to about 2 μM, fromabout 0.02 to about 20 μM, or from about 0.01 to about 20 μM.

In certain embodiments, the amount of the compound administered issufficient to provide an area under the curve (AUC) of the compound,ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 toabout 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, orfrom about 5,000 to about 10,000 ng*hr/mL.

In certain embodiments, the patient to be treated with one of themethods provided herein has not been treated with anticancer therapyprior to the administration of the compound provided herein, or aderivative thereof. In certain embodiments, the patient to be treatedwith one of the methods provided herein has been treated with anticancertherapy prior to the administration of the compound provided herein, ora derivative thereof. In certain embodiments, the patient to be treatedwith one of the methods provided herein has developed drug resistance tothe anticancer therapy.

The methods provided herein encompass treating a patient regardless ofpatient's age, although some diseases or disorders are more common incertain age groups.

Depending on the disease to be treated and the subject's condition, thecompound provided herein, or a derivative thereof, may be administeredby oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,CIV, intracistemal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topical(e.g., transdermal or local) routes of administration. The compoundprovided herein, or a derivative thereof, may be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants and vehicles, appropriate for each routeof administration.

In one embodiment, the compound provided herein, or a derivativethereof, is administered orally. In another embodiment, the compoundprovided herein, or a derivative thereof, is administered parenterally.In yet another embodiment, the compound provided herein, or a derivativethereof, is administered intravenously.

The compound provided herein, or a derivative thereof, can be deliveredas a single dose such as, e.g., a single bolus injection, or oraltablets or pills; or over time, such as, e.g., continuous infusion overtime or divided bolus doses over time. The compound can be administeredrepeatedly if necessary, for example, until the patient experiencesstable disease or regression, or until the patient experiences diseaseprogression or unacceptable toxicity. For example, stable disease forsolid tumors generally means that the perpendicular diameter ofmeasurable lesions has not increased by 25% or more from the lastmeasurement. Response Evaluation Criteria in Solid Tumors (RECIST)Guidelines, Journal of the National Cancer Institute 92(3): 205 216(2000). Stable disease or lack thereof is determined by methods known inthe art such as evaluation of patient symptoms, physical examination,visualization of the tumor that has been imaged using X-ray, CAT, PET,or MRI scan and other commonly accepted evaluation modalities.

The compound provided herein, or a derivative thereof, can beadministered once daily (QD), or divided into multiple daily doses suchas twice daily (BID), three times daily (TID), and four times daily(QID). In addition, the administration can be continuous (i.e., dailyfor consecutive days or every day), intermittent, e.g., in cycles (i.e.,including days, weeks, or months of rest without drug). As used herein,the term “daily” is intended to mean that a therapeutic compound, suchas the compound provided herein, or a derivative thereof, isadministered once or more than once each day, for example, for a periodof time. The term “continuous” is intended to mean that a therapeuticcompound, such as the compound provided herein or a derivative thereof,is administered daily for an uninterrupted period of at least 10 days to52 weeks. The term “intermittent” or “intermittently” as used herein isintended to mean stopping and starting at either regular or irregularintervals. For example, intermittent administration of the compoundprovided herein or a derivative thereof is administration for one to sixdays per week, administration in cycles (e.g., daily administration fortwo to eight consecutive weeks, then a rest period with noadministration for up to one week), or administration on alternate days.The term “cycling” as used herein is intended to mean that a therapeuticcompound, such as the compound provided herein or a derivative thereof,is administered daily or continuously but with a rest period. In somesuch embodiments, administration is once a day for two to six days, thena rest period with no administration for five to seven days.

In some embodiments, the frequency of administration is in the range ofabout a daily dose to about a monthly dose. In certain embodiments,administration is once a day, twice a day, three times a day, four timesa day, once every other day, twice a week, once every week, once everytwo weeks, once every three weeks, or once every four weeks. In oneembodiment, the compound provided herein, or a derivative thereof, isadministered once a day. In another embodiment, the compound providedherein, or a derivative thereof, is administered twice a day. In yetanother embodiment, the compound provided herein, or a derivativethereof, is administered three times a day. In still another embodiment,the compound provided herein, or a derivative thereof, is administeredfour times a day.

In certain embodiments, the compound provided herein, or a derivativethereof, is administered once per day from one day to six months, fromone week to three months, from one week to four weeks, from one week tothree weeks, or from one week to two weeks. In certain embodiments, thecompound provided herein, or a derivative thereof, is administered onceper day for one week, two weeks, three weeks, or four weeks. In oneembodiment, the compound provided herein, or a derivative thereof, isadministered once per day for 4 days. In one embodiment, the compoundprovided herein, or a derivative thereof, is administered once per dayfor 5 days. In one embodiment, the compound provided herein, or aderivative thereof, is administered once per day for 6 days. In oneembodiment, the compound provided herein, or a derivative thereof, isadministered once per day for one week. In another embodiment, thecompound provided herein, or a derivative thereof, is administered onceper day for two weeks. In yet another embodiment, the compound providedherein, or a derivative thereof, is administered once per day for threeweeks. In still another embodiment, the compound provided herein, or aderivative thereof, is administered once per day for four weeks.

Combination Therapy with a Second Active Agent

The compound provided herein, or a derivative thereof, can also becombined or used in combination with other therapeutic agents useful inthe treatment and/or prevention of cancer described herein.

In one embodiment, provided herein is a method of treating, preventing,or managing cancer, comprising administering to a patient a compoundprovided herein, or a derivative thereof; in combination with one ormore second active agents, and optionally in combination with radiationtherapy, blood transfusions, or surgery. Examples of second activeagents are disclosed herein.

As used herein, the term “in combination” includes the use of more thanone therapy (e.g., one or more prophylactic and/or therapeutic agents).However, the use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a patient with a disease or disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compoundprovided herein, a compound provided herein, e.g., the compound providedherein, or a derivative thereof) can be administered prior to (e.g., 5minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before),concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of asecond therapy (e.g., a prophylactic or therapeutic agent) to thesubject. Triple therapy is also contemplated herein.

Administration of the compound provided herein, or a derivative thereofand one or more second active agents to a patient can occursimultaneously or sequentially by the same or different routes ofadministration. The suitability of a particular route of administrationemployed for a particular active agent will depend on the active agentitself (e.g., whether it can be administered orally without decomposingprior to entering the blood stream) and the cancer being treated.

The route of administration of the compound provided herein, or aderivative thereof, is independent of the route of administration of asecond therapy. In one embodiment, the compound provided herein, or aderivative thereof, is administered orally. In another embodiment, thecompound provided herein, or a derivative thereof, is administeredintravenously. Thus, in accordance with these embodiments, the compoundprovided herein, or a derivative thereof, is administered orally orintravenously, and the second therapy can be administered orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form. In one embodiment, the compound provided herein, or aderivative thereof, and a second therapy are administered by the samemode of administration, orally or by IV. In another embodiment, thecompound provided herein, or a derivative thereof, is administered byone mode of administration, e.g., by IV, whereas the second agent (ananticancer agent) is administered by another mode of administration,e.g., orally.

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount of the compound provided herein, or a derivative thereof, andany optional additional active agents concurrently administered to thepatient.

One or more second active ingredients or agents can be used togetherwith the compound provided herein, or a derivative thereof, in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies, particularly, therapeutic antibodies to cancerantigens. Typical large molecule active agents are biological molecules,such as naturally occurring or synthetic or recombinant proteins.Proteins that are particularly useful in the methods and compositionsprovided herein include proteins that stimulate the survival and/orproliferation of hematopoietic precursor cells and immunologicallyactive poietic cells in vitro or in vivo. Other useful proteinsstimulate the division and differentiation of committed erythroidprogenitors in cells in vitro or in vivo. Particular proteins include,but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; GM-CF and GM-CSF; and EPO.

In certain embodiments, GM-CSF, G-CSF, SCF or EPO is administeredsubcutaneously during about five days in a four or six week cycle in anamount ranging from about 1 to about 750 mg/m²/day, from about 25 toabout 500 mg/m²/day, from about 50 to about 250 mg/m²/day, or from about50 to about 200 mg/m²/day. In certain embodiments, GM-CSF may beadministered in an amount of from about 60 to about 500 mcg/m²intravenously over 2 hours or from about 5 to about 12 mg/m²/daysubcutaneously. In certain embodiments, G-CSF may be administeredsubcutaneously in an amount of about 1 mcg/kg/day initially and can beadjusted depending on rise of total granulocyte counts. The maintenancedose of G-CSF may be administered in an amount of about 300 (in smallerpatients) or 480 mcg subcutaneously. In certain embodiments, EPO may beadministered subcutaneously in an amount of 10,000 Unit 3 times perweek.

Particular proteins that can be used in the methods and compositionsinclude, but are not limited to: filgrastim, which is sold in the UnitedStates under the trade name Neupogen® (Amgen, Thousand Oaks, Calif.);sargramostim, which is sold in the United States under the trade nameLeukine® (Immunex, Seattle, Wash.); and recombinant EPO, which is soldin the United States under the trade name Epogen® (Amgen, Thousand Oaks,Calif.).

Recombinant and mutated forms of GM-CSF can be prepared as described inU.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which areincorporated herein by reference. Recombinant and mutated forms of G-CSFcan be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291;5,528,823; and 5,580,755; the entireties of which are incorporatedherein by reference.

Also provided for use in combination with a compound provided herein, ora derivative thereof, of are native, naturally occurring, andrecombinant proteins. Further encompassed are mutants and derivatives(e.g., modified forms) of naturally occurring proteins that exhibit, invivo, at least some of the pharmacological activity of the proteins uponwhich they are based. Examples of mutants include, but are not limitedto, proteins that have one or more amino acid residues that differ fromthe corresponding residues in the naturally occurring forms of theproteins. Also encompassed by the term “mutants” are proteins that lackcarbohydrate moieties normally present in their naturally occurringforms (e.g., nonglycosylated forms). Examples of derivatives include,but are not limited to, pegylated derivatives and fusion proteins, suchas proteins formed by fusing IgG1 or IgG3 to the protein or activeportion of the protein of interest. See, e.g., Penichet, M. L. andMorrison, S. L., J. Immunol. Methods 248:91-101 (2001).

Antibodies that can be used in combination with a compound providedherein, or a derivative thereof, include monoclonal and polyclonalantibodies. Examples of antibodies include, but are not limited to,trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (Avastin™)pertuzumab (Omnitarg™), tositumomab (Bexxar®), edrecolomab (Panorex®),and G250. The compounds provided herein or an enantiomer or a mixture ofenantiomers thereof, or a pharmaceutically acceptable salt, solvate,hydrate, co-crystal, clathrate, or polymorph thereof can also becombined with, or used in combination with, anti-TNF-α antibodies,and/or anti-EGFR antibodies, such as, for example, Erbitux® orpanitumumab.

Large molecule active agents may be administered in the form ofanti-cancer vaccines. For example, vaccines that secrete, or cause thesecretion of, cytokines such as IL-2, G-CSF, and GM-CSF can be used inthe methods and pharmaceutical compositions provided. See, e.g., Emens,L. A., et al., Curr. Opinion Mol. Ther. 3(1):77-84 (2001).

Second active agents that are small molecules can also be used toalleviate adverse effects associated with the administration of acompound provided herein, or a derivative thereof. However, like somelarge molecules, many are believed to be capable of providing asynergistic effect when administered with (e.g., before, after orsimultaneously) a compound provided herein, or a derivative thereof.Examples of small molecule second active agents include, but are notlimited to, anti-cancer agents, antibiotics, immunosuppressive agents,and steroids.

In certain embodiments, the second agent is an HSP inhibitor, aproteasome inhibitor, a FLT3 inhibitor or a TOR kinase inhibitor.

Examples of anti-cancer agents to be used within the methods orcompositions described herein include, but are not limited to: acivicin;aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole;anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin;batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafidedimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;busulfan; cactinomycin; calusterone; caracemide; carbetimer;carboplatin; carmustine; carubicin hydrochloride; carzelesin;cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin;cisplatin; cladribine; clofarabine; crisnatol mesylate;cyclophosphamide; Ara-C; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; omacetaxine; ormaplatin; oxisuran;paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sorafenib; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other anti-cancer drugs to be included within the methods orcompositions include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; Ara-C ocfosfate; cytolytic factor; cytostatin;dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox;diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin;diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib(e.g., Gleevec®); imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryllipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®);O6 benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine;romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin;SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;senescence derived inhibitor 1; sense oligonucleotides; signaltransduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine;tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomeraseinhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; translation inhibitors; tretinoin;triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;ubenimex; urogenital sinus-derived growth inhibitory factor; urokinasereceptor antagonists; vapreotide; variolin B; velaresol; veramine;verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents particularly useful in the methods orcompositions include, but are not limited to, rituximab, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,Ara-C, doxetaxol, pacilitaxel, vinblastine, IL-2, GM CSF, dacarbazine,vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan,prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin(Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodiumphosphate (Emcyt®), sulindac, and etoposide.

In certain embodiments of the methods provided herein, use of a secondactive agent in combination with a compound provided herein, or aderivative thereof, may be modified or delayed during or shortlyfollowing administration of a compound provided herein, or a derivativethereof, as deemed appropriate by the practitioner of skill in the art.In certain embodiments, subjects being administered a compound providedherein, or a derivative thereof, alone or in combination with othertherapies may receive supportive care including antiemetics, myeloidgrowth factors, and transfusions of platelets, when appropriate. In someembodiments, subjects being administered a compound provided herein, ora derivative thereof, may be administered a growth factor as a secondactive agent according to the judgment of the practitioner of skill inthe art. In some embodiments, provided is administration of a compoundprovided herein, or a derivative thereof, in combination witherythropoietin or darbepoetin (Aranesp).

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with gemcitabine and cisplatinum to patientswith locally advanced or metastatic transitional cell bladder cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with a second active ingredientas follows: temozolomide to pediatric patients with relapsed orprogressive brain tumors or recurrent neuroblastoma; celecoxib,etoposide and cyclophosphamide for relapsed or progressive CNS cancer;temodar to patients with recurrent or progressive meningioma, malignantmeningioma, hemangiopericytoma, multiple brain metastases, relapasedbrain tumors, or newly diagnosed glioblastoma multiforms; irinotecan topatients with recurrent glioblastoma; carboplatin to pediatric patientswith brain stem glioma; procarbazine to pediatric patients withprogressive malignant gliomas; cyclophosphamide to patients with poorprognosis malignant brain tumors, newly diagnosed or recurrentglioblastoma multiforms; Gliadel® for high grade recurrent malignantgliomas; temozolomide and tamoxifen for anaplastic astrocytoma; ortopotecan for gliomas, glioblastoma, anaplastic astrocytoma oranaplastic oligodendroglioma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with methotrexate, cyclophosphamide, taxane,abraxane, lapatinib, herceptin, aromatase inhibitors, selective estrogenmodulators, estrogen receptor antagonists, and/or PLX3397 (Plexxikon) topatients with metastatic breast cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with temozolomide to patients withneuroendocrine tumors.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with gemcitabine to patients with recurrent ormetastatic head or neck cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with gemcitabine to patients with pancreaticcancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with colon cancer in combinationwith ARISA®, avastatin, taxol, and/or taxotere.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with capecitabine and/or PLX4032 (Plexxikon) topatients with refractory colorectal cancer or patients who fail firstline therapy or have poor performance in colon or rectal adenocarcinoma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with fluorouracil, leucovorin,and irinotecan to patients with Dukes C & D colorectal cancer or topatients who have been previously treated for metastatic colorectalcancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with refractory colorectal cancerin combination with capecitabine, xeloda, and/or CPT-11.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with capecitabine and irinotecan to patientswith refractory colorectal cancer or to patients with unresectable ormetastatic colorectal carcinoma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered alone or in combination with interferon alphaor capecitabine to patients with unresectable or metastatichepatocellular carcinoma; or with cisplatin and thiotepa to patientswith primary or metastatic liver cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with pegylated interferon alphato patients with Kaposi's sarcoma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with fludarabine, carboplatin,and/or topotecan to patients with refractory or relapsed or high-riskacute myeloid leukemia.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with liposomal daunorubicin,topotecan and/or cytarabine to patients with unfavorable karotype acutemyeloblastic leukemia.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with gemcitabine, abraxane,erlotinib, geftinib, and/or irinotecan to patients with non-small celllung cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with carboplatin and irinotecanto patients with non-small cell lung cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered with doxetaxol to patients with non-small celllung cancer who have been previously treated with carbo/VP 16 andradiotherapy.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with carboplatin and/ortaxotere, or in combination with carboplatin, pacilitaxel and/orthoracic radiotherapy to patients with non-small cell lung cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with taxotere to patients withstage IIIB or IV non-small cell lung cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with oblimersen (Genasense®) topatients with small cell lung cancer.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with ABT-737 (AbbottLaboratories) and/or obatoclax (GX15-070) to patients with lymphoma andother blood cancers.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered alone or in combination with a second activeingredient such as vinblastine or fludarabine to patients with varioustypes of lymphoma, including, but not limited to, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma or relapsed or refractory lowgrade follicular lymphoma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with taxotere, IL-2, IFN,GM-CSF, PLX4032 (Plexxikon) and/or dacarbazine to patients with varioustypes or stages of melanoma.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered alone or in combination with vinorelbine topatients with malignant mesothelioma, or stage IIIB non-small cell lungcancer with pleural implants or malignant pleural effusion mesotheliomasyndrome.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with various types or stages ofmultiple myeloma in combination with dexamethasone, zoledronic acid,palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan,cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate,celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a combinationthereof.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with relapsed or refractorymultiple myeloma in combination with doxorubicin (Doxil®), vincristineand/or dexamethasone (Decadron®).

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with various types or stages ofovarian cancer such as peritoneal carcinoma, papillary serous carcinoma,refractory ovarian cancer or recurrent ovarian cancer, in combinationwith taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda,paclitaxel, dexamethasone, or a combination thereof.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with various types or stages ofprostate cancer, in combination with xeloda, 5 FU/LV, gemcitabine,irinotecan plus gemcitabine, cyclophosphamide, vincristine,dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel,adriamycin, docetaxel, estramustine, Emcyt, denderon or a combinationthereof.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with various types or stages ofrenal cell cancer, in combination with capecitabine, IFN, tamoxifen,IL-2, GM-CSF, Celebrex®, or a combination thereof.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with various types or stages ofgynecologic, uterus or soft tissue sarcoma cancer in combination withIFN, a COX-2 inhibitor such as Celebrex®, and/or sulindac.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with various types or stages ofsolid tumors in combination with celebrex, etoposide, cyclophosphamide,docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combinationthereof.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with scleroderma or cutaneousvasculitis in combination with celebrex, etoposide, cyclophosphamide,docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combinationthereof.

Also encompassed herein is a method of increasing the dosage of ananti-cancer drug or agent that can be safely and effectivelyadministered to a patient, which comprises administering to the patient(e.g., a human) a compound provided herein, or a derivative thereof.Patients that can benefit by this method are those likely to suffer froman adverse effect associated with anti-cancer drugs for treating aspecific cancer of the skin, subcutaneous tissue, lymph nodes, brain,lung, liver, bone, intestine, colon, heart, pancreas, adrenal, kidney,prostate, breast, colorectal, or combinations thereof. Theadministration of a compound provided herein, or a derivative thereof,alleviates or reduces adverse effects which are of such severity that itwould otherwise limit the amount of anti-cancer drug.

In one embodiment, a compound provided herein, or a derivative thereof,is administered orally and daily in an amount ranging from about 0.1 toabout 150 mg, from about 1 to about 50 mg, or from about 2 to about 25mg, prior to, during, or after the occurrence of the adverse effectassociated with the administration of an anti-cancer drug to a patient.In certain embodiments, a compound provided herein, or a derivativethereof, is administered in combination with specific agents such asheparin, aspirin, coumadin, or G CSF to avoid adverse effects that areassociated with anti-cancer drugs such as but not limited to neutropeniaor thrombocytopenia.

In one embodiment, a compound provided herein, or a derivative thereof,is administered to patients with diseases and disorders associated withor characterized by, undesired angiogenesis in combination withadditional active ingredients, including, but not limited to,anti-cancer drugs, anti-inflammatories, antihistamines, antibiotics, andsteroids.

In another embodiment, encompassed herein is a method of treating,preventing and/or managing cancer, which comprises administering thecompound provided herein, or a derivative thereof, in conjunction with(e.g. before, during, or after) conventional therapy including, but notlimited to, surgery, immunotherapy, biological therapy, radiationtherapy, or other non-drug based therapy presently used to treat,prevent or manage cancer. The combined use of the compound providedherein, or a derivative thereof, and conventional therapy may provide aunique treatment regimen that is unexpectedly effective in certainpatients. Without being limited by theory, it is believed that thecompound provided herein, or a derivative thereof, may provide additiveor synergistic effects when given concurrently with conventionaltherapy.

As discussed elsewhere herein, encompassed herein is a method ofreducing, treating and/or preventing adverse or undesired effectsassociated with conventional therapy including, but not limited to,surgery, chemotherapy, radiation therapy, hormonal therapy, biologicaltherapy and immunotherapy. A compound provided herein, or a derivativethereof, and other active ingredient can be administered to a patientprior to, during, or after the occurrence of the adverse effectassociated with conventional therapy.

In one embodiment, the compound provided herein, or a derivativethereof, can be administered in an amount ranging from about 0.1 toabout 150 mg, from about 1 to about 25 mg, or from about 2 to about 10mg orally and daily alone, or in combination with a second active agentdisclosed herein (see, e.g., section 5.4), prior to, during, or afterthe use of conventional therapy.

In certain embodiments, a compound provided herein, or a derivativethereof, and doxetaxol are administered to patients with non-small celllung cancer who were previously treated with carbo/VP 16 andradiotherapy.

In certain embodiments, a compound provided herein, or a derivativethereof, is administered to patients with various types or stages ofcancer, in combination with an immune oncology drug or a combination ofimmune oncology drugs. In one embodiment, a compound provided herein, ora derivative thereof, is administered to patients with various types orstages of cancer, in combination with Opdivo, Keytruda, Yervoy or acombination thereof.

7.2 Inflammation

As discussed herein, activation of MAPKs is a component of theinflammatory response. Thus, the compounds provided herein, which areMAPK inhibitors, are useful in the treatment of inflammatory diseases.

In one embodiment, the inflammatory disease is inflammation-associatedcancer development. As disclosed here, the compounds provided herein areuseful in treatment of cancer. It is well recognized that the immuneinflammatory state serves as a key mediator of the middle stages oftumor development. It is also well known that chronic inflammation canpredispose an individual to cancer. Chronic inflammation is caused by avariety of factors, including bacterial, viral, and parasiticinfections. The longer the inflammation persists, the higher the risk ofassociated carcinogenesis. Anti-inflammatory cancer therapy preventspremalignant cells from turning fully cancerous or impede existingtumors from spreading to distant sites in the body. Thus, in oneembodiment, the compounds provided herein are useful in treatinginflammatory cancers. Such cancers, and the chronic inflammatoryconditions that predispose susceptible cells to neoplastictransformation, include gastric adenocarcinoma (gastritis),mucosa-associated lymphoid tissue (MALT) lymphoma (gastritis), bladder,liver and rectal carcinomas (schistosomiasis), cholangiocarcinoma andcolon carcinoma (cholangitis), gall bladder cancer (chroniccholecystitis), ovarian and cervical carcinoma (pelvic inflammatorydisease, chronic cervicitis), skin carcinoma (osteomyelitis), colorectalcarcinoma (inflammatory bowel disease), esophageal carcinoma (refluxesophagitis, Barrett's esophagus), bladder cancer (bladder inflammation(cystitis)), mesothelioma and lung carcinoma (asbestosis, silicosis),oral squamous cell carcinoma (gingivitis, lichen planus), pancreaticcarcinoma (pancreatitis, protease mutation), vulvar squamous cellcarcinoma (lichen sclerosis), salivary gland carcinoma (slaladenitis),lung carcinoma (bronchitis) and MALT lymphoma (Sjogren syndrome,Hashimoto's thyroiditis). Shacter, et al., 2002, Oncology, 16(2),217-26.

In certain embodiments, the compounds provided herein are useful intreating inflammatory diseases in the airways, such as nonspecificbronchial hyper-reactivity, chronic bronchitis, cystic fibrosis, andacute respiratory distress syndrome (ARDS).

In certain embodiments, the compounds provided herein are useful intreating asthma and idiopathic lung fibrosis or idiopathic pulmonaryfibrosis (IPF), pulmonary fibrosis, and interstitial lung disease. Asknown to one of skill in the art, the differentiation of fibroblastsinto cell types called myofibroblasts occurs during wound healing, whenthe cells contribute to the deposition of extracellular matrix (ECM) inthe transient process of wound repair. In chronic inflammatory diseasessuch as asthma, pathological tissue remodeling often occurs, and ismediated by the functions of increased numbers of myofibroblasts in thediseased tissue, see Hinz, B. et al. Am J Pathol. 2007; 170: 1807-1816.In certain embodiments, the compounds provided herein prevent or reduceTGF-β-induced myofibroblast differentiation, as measured by theexpression of alpha smooth muscle actin (α-SMA), a hallmark ofmyofibroblast differentiation (Serini, G. and Gabbiani, G. 1999; Exp.Cell Res. 250: 273-283).

In certain embodiments, the compounds provided herein are useful intreating psoriasis, chronic plaque psoriasis, psoriatic arthritis,acanthosis, atopic dermatitis, various forms of eczema, contactdermatitis (includes allergic dermatitis), systemic sclerosis(scleroderma), wound healing, and drug eruption.

In one embodiment, the disease is inflammation, arthritis, rheumatoidarthritis, spondylarthropathies, gouty arthritis, osteoarthritis,juvenile arthritis, and other arthritic conditions, systemic lupuserthematosus (SLE), skin-related conditions, eczema, Sjögren's syndrome,burns, dermatitis, neuroinflammation, allergy pain, autoimmune myositis,neuropathic pain, fever, pulmonary disorders, lung inflammation, adultrespiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis,chronic pulmonary inflammatory disease, and chronic obstructivepulmonary disease (COPD), cardiovascular disease, arteriosclerosis,myocardial infarction (including post-myocardial infarctionindications), thrombosis, congestive heart failure, cardiac reperfusioninjury, as well as complications associated with hypertension and/orheart failure such as vascular organ damage, restenosis, cardiomyopathy,stroke including ischemic and hemorrhagic stroke, reperfusion injury,renal reperfusion injury, ischemia including stroke and brain ischemia,and ischemia resulting from cardiac/coronary bypass, neurodegenerativedisorders, liver disease and nephritis, gastrointestinal conditions,inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, viraland bacterial infections, sepsis, septic shock, gram negative sepsis,malaria, meningitis, HIV infection, opportunistic infections, cachexiasecondary to infection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex),pneumonia, herpes virus, myalgias due to infection, influenza,autoimmune disease, graft vs. host reaction and allograft rejections,treatment of bone resorption diseases, osteoporosis, multiple sclerosis,acute gout, pneumonitis, myocarditis, pericarditis, myositis, eczema,alopecia, vitiligo, bullous skin diseases, atherosclerosis, depression,retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliarycirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis,thyroiditis, type I diabetes, giant cell arteritis, nephritis includinglupus nephritis, vasculitis with organ involvement such asglomerulonephritis, vasculitis including giant cell arteritis, Wegener'sgranulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasakidisease, Takayasu's Arteritis, vasculitis with organ involvement, acuterejection of transplanted organs. endotoxaemia, systemic inflammatoryresponse syndrome (SIRS), multi-organ dysfunction syndrome, toxic shocksyndrome, acute lung injury, ARDS (adult respiratory distress syndrome),acute renal failure, fulminant hepatitis, burns, acute pancreatitis,postsurgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis,myelitis, SIRS associated with viral infections such as influenza,herpes zoster, herpes simplex, coronavirus or dry eye syndrome (orkeratoconjunctivitis sicca (KCS)).

In certain embodiments, the compounds provided herein are useful intreating neuropathic and nociceptive pain, chronic or acute, such as,without limitation, allodynia, inflammatory pain, inflammatoryhyperalgesia, post herpetic neuralgia, neuropathies, neuralgia, diabeticneuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthriticpain, osteoarthritic pain, burns, back pain, ocular pain, visceral pain,cancer pain, dental pain, headache, migraine, carpal tunnel syndrome,fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain,post operative pain, post stroke pain, and menstrual pain.

In certain embodiments, the compounds provided herein are useful intreating Alzheimer's disease (AD), mild cognitive impairment (MCI),age-associated memory impairment (AAMI), multiple sclerosis, Parkinson'sdisease, vascular dementia, senile dementia, AIDS dementia, Pick'sdisease, dementia caused by cerebrovascular disorders, corticobasaldegeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease,diminished CNS function associated with traumatic brain injury.

When used for the treatment of inflammatory disease, the compoundsprovided herein may be administered in dosages, routes of administrationand/or to achieve pK profiles as described herein for the treatment ofcancer.

8. EXAMPLES

The following examples are offered to illustrate but not to limit thedisclosure.

Example 1 Protocol for MAPK Cell-Based Phosphorylation Assay

Cell lines: Tumor-derived pancreatic cancer cell lines PANC-1 werepurchased from ATCC and were maintained according to ATCCrecommendation.

Method: Cells were plated at 7500 cells/well density in 96-wells plate,starved ON, and the small molecules to be tested were added to the cellsin the final concentration of 30 μM with 0.3% DMSO for 6 hoursincubation at 37° C. Next, cells were stimulated with 1.5 ng/ml EGF for15 min. followed by cell fixation with 4% Formaldehyde in PBS at RT for20 min. Phosphorylation level of MAPK was determined by Cell-directELISA.

Cell-direct ELISA: For each well, cells were permeabilized withPBS-Triton 0.1%, quenched with H₂O₂ 0.6% in PBS-Triton 0.1%, and probedwith anti-phospho-MAPK antibodies (R&D Systems) followed byHRP-conjugated secondary antibody (Jackson Immunoresearch, West Grove,Pa.). Next, a solution 50 μM of the fluorescent substrate AmpliFlu Red(Sigma) was added and incubated at RT for 20 min. At the end of theincubation time, fluorescence was measured at 595 nm on a microplatereader (AF2200; Eppendorf, Inc., Hamburg, Germany).

Table 2 shows inhibition data for selected compounds tested in thecellular assay described above.

TABLE 2 % Inhibition of MAPK phosphorylation @ 30 μM in the PANC-1pancreatic cancer cell line Compound PANC-1

B

A

C

A

C

A

A

A

A

B

A

A

A

A

A

B

A

B

A

A

A

C

B

A

A

C

A

A

A

A

A

A

B

A

A

A

B

A

A

B

A

A

B

A

B

B

D

A

D

D

B

A

A

B

A

D

A

A

B

A

A

B

A

D

A

A

B

A

B

A

A

A

D

A

A

A

D

B

A

A

B

A

D

D

A

A

A

A

D

A

A

D

C

A

D

A

A

B

B

D

A

A

A

B

B

B

B

A

A

D

C

A

A

A

A

A

D

B

B

A

D

A A = 1-25% inhibition, B = 25-50% inhibition, C = 51-75% inhibition, D= 76-100% inhibition

Example 2 Protocol for Cell Proliferation Assay

Cell lines: Tumor-derived pancreatic cancer cell lines MIA-PACA2 werepurchased from ATCC and grown in complete DMEM-High Glucose mediumsupplemented with penicillin (100 U/mL), streptomycin (100 μg/mL), and10% heat-inactivated FBS at 37° C. in a humidified incubator with 5%CO2.

Method: Cells are plated at 1000 cells/well density in 96-wells plate,starved ON, and the next day tested small molecules are added to thecells in the final concentration of 30 μM with 0.3% DMSO 3 hours priorto 10% FBS addition. After serum addition cells are incubated for 6 daysat 37° C. in a humidified incubator with 5% CO₂.

Assay: At the end of the incubation period, cell cultures are testedusing the CellTiter 96® AQueous One Solution Cell Proliferation Assaykit (Promega Corporation, Madison, Wis.) according to the manufacturerspecifications. Briefly, assay is performed by adding 20 μl of theCellTiter 96 Aqueous One Solution Reagent directly to culture wells,followed by for 1-4 hours incubation at 37° C. in a humidified incubatorwith 5% CO₂. At the end of incubation time, absorbance at 492 nm isrecorded with the 96-well plate reader Eppendorf AF2200, and degree ofsmall molecule-dependent proliferation inhibition is calculated from rawdata assuming No Serum cells value as 100%.

Table 3 shows inhibition data for selected compounds tested in thecellular assay described above.

TABLE 3 % Inhibition of cell proliferation @ 30 μM in MIA-PACA2pancreatic cancer cell lines MIA- Compound PACA2

D

B

A

D

A

C

A

B

C

C

D

D

D

D

D

C

D

C

B

B

D

D

A

B

C

D

A

C

B

B

A

C

A

D

D

D

C

C

D

A

D

D

D

D

C

C

B

D

D

C

D

D

B

C

D

A

D

B

B

D

D

D

C

C

B

B

C

A

D

A

D

D

B

B

D

D

D

D

C

A

D

C

D

C

A

D

D

B

A

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

C

D

D

A

D

D

C

A

D

D

D

D

D

D

D

D

A

D

D

D

D

B

D

D

D

D

D

D

D

A

D

D

D

D

D

D

D

D

D

C

D

B

D

A

D

C

C

D

A

D

C

A

D

D

D

D

D

D

A

D

A

A

B

D

D

D

A

A

B

A

A

D

D

D

D

D

A

A

D

D

D

D

A

C

B

A

B

D

D

B

D

D

B

D

A

D

B

C

D

D

D

D

A

C

D

D

D

D

D

D

D

D

D

D

D

D

A

D

C

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

D

A

A A = 1-25% inhibition, B = 25-50% inhibition, C = 51-75% inhibition, D= 76-100% inhibition

Example 3 Protocol for Mouse TNF Alpha and IL6 Quantification Assay

Cell lines: Abelson murine leukemia virus transformed macrophage cellline RAW 264.7 was purchased from ATCC and grown in complete DMEM-HighGlucose medium supplemented with penicillin (100 U/mL), streptomycin(100 μg/mL), and 10% heat-inactivated FBS at 37° C. in a humidifiedincubator with 5% CO₂.

Method: Cells were plated at 40000 cells/well density in a 96-wellsplate. After a 3-hour incubation, macrophages were starved with DMEMplus 0.5% FBS o/n. The next day the small molecules to be tested wereadded to the cells in the final concentration of 30 μM (with 0.3% DMSO)3 hours prior to LPS stimulation (100 ng/ml). After LPS stimulationcells were incubated at 37° C. for 16 h. At the end of the incubationperiod, culture media were collected and production of LPS-induced TNFαand IL6 cytokine was measured using ELISA detection kits.

Sandwich ELISA: The ELISA Immunoassays Quantikine Mouse TNF-alpha(catalog number MTA00B) and IL6 (catalog number M6000B) were purchasedfrom R&D Systems Inc., Minneapolis, Minn. These 4.5 hours solid phaseELISAs were used to measure mouse TNFα or IL6 levels in macrophagesculture supernatants. Assays were executed according to the manufacturerspecifications.

Table 4 shows inhibition data for selected compounds tested in thecellular assay described above.

TABLE 4 IL-6 and TNFα % Inhibition @ 30 μM in RAW 264.7 murine leukemiavirus transformed macrophage cell lines Compound IL-6 TNF-α

B A

0 A

0 A

0 A

A B

A 0

B A

0 A

B A

A A

A A

0 A

B A

B 0

A 0

B A

C 0

A 0

A 0

C A

0 A

A 0

C A

0 A

A 0

0 A

0 A

A 0

A A

A 0

B A

B A

A 0

A 0

0 A

A 0

A 0

A A

B A

A 0

A 0

0 A

A 0

A 0

0 A

A A

A 0

A 0

B A

A A

A 0

A 0

A A

A 0

A A

0 A

A A

B 0

A 0

0 A

B A

B A

A A

B A

A A

0 A

A 0

B A

A 0

C 0

C A

B A

0 A

0 A

B 0

B 0

A 0

B A

B A

B A

0 A

A 0

0 A

A 0

D 0

C 0

C 0

B A

0 A

C A

C A

B A

A A

A A

B A

B B

A 0

D C

B A

0 A

0 A

0 A

A 0

C D

A A

D D

A A

A A

B B

0 A

0 A

0 A

0 A

A 0

D D

D D

B 0

B A

B A

A A

A A

B 0

B A

B A

A 0

A 0

A 0

0 A

C 0

B B

D D

0 A

C A

0 A

A A

0 A

A C

C 0

B 0

A A

B 0

B B

A B

0 A

A 0

B A

D A

C A

D B

A 0

D A

D B

D A

D A

C 0

D A

A A

B 0

B 0

0 A

D B

B 0

A A

D A

A A

A A

0 A

0 A

0 A

A 0

0 A

A 0

A 0

A A

A A

D D

B 0

D A

D A

C A

A 0

A B

D C

A 0

D A

C 0

A 0

C 0

B 0

C 0

B 0

C 0

B A

A 0

B 0

D D

D C

D D

A 0

B 0

A A

C 0

A A

D D

C A

A 0

A A

D D

D D

A 0

D D

D D

B B

A A

D C

C B

D B

D C

D D

A A

A A

A A

B A

B A

B B

D C

D B

A 0

B 0

B A

A A

B A

A A

D B

C B

A A

D D

B B

A A

A A

D D

A A 0 = 0% inhibition, A = 1-25% inhibition, B = 26-50% inhibition, C =51-75% inhibition, D = 76-100% inhibition

This disclosure is not to be limited in scope by the embodimentsdisclosed in the examples which are intended as single illustrations ofindividual aspects, and any methods which are functionally equivalentare within the scope of this disclosure. Indeed, various modificationsin addition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

Various references such as patents, patent applications, andpublications are cited herein, the disclosures of which are herebyincorporated by reference herein in their entireties.

1-5. (canceled)
 6. A compound of Formula VIf:

or a pharmaceutically acceptable salt thereof, wherein R^(1f) is 2-pyridyl; and R^(2f) is —C(O)R, wherein R is aryl, heteroaryl or alkyl.
 7. (canceled)
 8. A method of treating, preventing or ameliorating one or more symptoms of cancer, comprising administering to a subject the compound or pharmaceutically acceptable salt thereof of claim
 6. 9. The method of claim 8, wherein the cancer is a solid tumor.
 10. The method of claim 9, wherein the solid tumor is hepatocellular carcinoma, prostate cancer, pancreatic cancer, ovarian cancer, or glioblastoma.
 11. The method of claim 10, wherein the solid tumor is pancreatic cancer.
 12. A method of treating, preventing or ameliorating one or more symptoms of an inflammatory disease, comprising administering to a subject the compound or pharmaceutically acceptable salt thereof of claim
 6. 13. The method of claim 12, wherein the inflammatory disease is gastritis, schistosomiasis, cholangitis, chronic cholecystitis, pelvic inflammatory disease, chronic cervicitis, osteomyelitis, inflammatory bowel disease, reflux esophagitis, Barrett's esophagus, bladder inflammation (cystitis), asbestosis, silicosis, gingivitis, lichen planus, pancreatitis, protease mutation, lichen sclerosis, slaladenitis, bronchitis, Sjogren syndrome or Hashimoto's thyroiditis.
 14. A pharmaceutical composition, comprising the compound or pharmaceutically acceptable salt thereof of claim 6 and a pharmaceutically acceptable carrier.
 15. The compound or pharmaceutically acceptable salt thereof of claim 6, wherein the compound is selected from the group consisting of:


16. A method of treating, preventing or ameliorating one or more symptoms of cancer, comprising administering to a subject the compound or pharmaceutically acceptable salt thereof of claim
 15. 17. The method of claim 16, wherein the cancer is a solid tumor.
 18. The method of claim 17, wherein the solid tumor is hepatocellular carcinoma, prostate cancer, pancreatic cancer, ovarian cancer, or glioblastoma.
 19. The method of claim 18, wherein the solid tumor is pancreatic cancer.
 20. A method of treating, preventing or ameliorating one or more symptoms of an inflammatory disease, comprising administering to a subject the compound or pharmaceutically acceptable salt thereof of claim
 15. 21. The method of claim 20, wherein the inflammatory disease is gastritis, schistosomiasis, cholangitis, chronic cholecystitis, pelvic inflammatory disease, chronic cervicitis, osteomyelitis, inflammatory bowel disease, reflux esophagitis, Barrett's esophagus, bladder inflammation (cystitis), asbestosis, silicosis, gingivitis, lichen planus, pancreatitis, protease mutation, lichen sclerosis, slaladenitis, bronchitis, Sjogren syndrome or Hashimoto's thyroiditis.
 22. A pharmaceutical composition, comprising the compound or pharmaceutically acceptable salt thereof of claim 15 and a pharmaceutically acceptable carrier. 